[Research progress on liposome and nanomicelle targeted drug delivery system across blood-brain barrier].

The blood-brain barrier(BBB), a protective barrier between brain tissues and brain capillaries, can prevent drugs from entering the brain tissues to exert the effect, which greatly increases the difficulty in treating brain diseases. The drug delivery system across the BBB can allow efficient drug delivery across the BBB by virtue of carriers and formulations, thereby enhancing the therapeutic effect of drugs on brain tissue diseases. Liposomes and micelles have been extensively studied with advances in the targeted therapy across the BBB for the brain due to their unique structures and drug delivery advantages. This study summarized the research status of liposome and micelle drug delivery systems across the BBB based on the literature in recent years and analyzed their application advantages and mechanism in terms of trans-BBB capability, targeting, and safety. Moreover, the problems and possible countermeasures in the research on trans-BBB liposomes and micelles were discussed according to the current clinical translation, which may provide refe-rences and ideas for the development of trans-BBB targeted nano-drugs.

Halolysin R4 of Haloferax mediterranei confers its host antagonistic and defensive activities.

Halolysins, which are subtilisin-like serine proteases of haloarchaea, are usually secreted into the extracellular matrix via the twin-arginine translocation pathway. A small number of activated molecules can greatly affect cell growth owing to their proteolytic activity. It is, however, unclear as to whether this proteolysis-based growth inhibition by halolysins conveys antagonistic or defensive effects against other resident abd potentially competitive microorganisms. Here, we report that halolysin R4 (HlyR4), encoded by the hlyR4 gene, is the key enzyme in the initial steps of extracellular protein utilization in Haloferax mediterranei HlyR4 shows significant antagonistic activity against other haloarchaeal strains. Deletion of hlyR4 completely halts the inhibition activity of Hfx. mediterranei towards other haloarchaea, while correspondingly, complementation of hlyR4 almost completely restores the inhibition activity. Furthermore, Hfx. mediterranei strains containing hlyR4 showed a certain amount of resistance to halocins and halolysins in milieu, and this function of hlyR4 is reproducible in Haloarcula hispanica The versatility of HlyR4 enables its host to outcompete other haloarchaea living in the same hypersaline environment. Intriguingly, unlike the growth phase-dependent halolysins SptA and Nep, it is likely that HlyR4 may be secreted independent of growth phase. This study provides a new peptide antibiotics candidate in haloarchaea, as well as new insight towards a better understanding of the ecological roles of halolysins.Importance: This study shows that halolysin R4 from Haloferax mediterranei provides its host antagonistic and defensive activities against other haloarchaea, which expands our knowledge on the traditional function of haloarchaeal extracellular proteases. Haloarchaeal extracellular serine proteases have been previously discussed as growth-phase-dependent proteins, whereas our study reports constitutive expression of halolysin R4. This work also clearly reveals a hidden diversity of extracellular proteases from haloarchaea. Studies on multifunctional halolysins reveal that they play an important ecological role in shaping microbial community composition and provide a new perspective towards understanding the intricate interactions between haloarchaeal cells in hypersaline environments. HlyR4 can lyse competing cells living in the same environment, and the cell debris may probably be utilized as nutrients, which may constitute an important part of nutrient cycling in extremely hypersaline environments.

H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin.

The histone variants H3.3 and H2A.Z have recently emerged as two of the most important features in transcriptional regulation, the molecular mechanism of which still remains poorly understood. In this study, we investigated the regulation of H3.3 and H2A.Z on chromatin dynamics during transcriptional activation. Our in vitro biophysical and biochemical investigation showed that H2A.Z promoted chromatin compaction and repressed transcriptional activity. Surprisingly, with only four to five amino acid differences from the canonical H3, H3.3 greatly impaired higher-ordered chromatin folding and promoted gene activation, although it has no significant effect on the stability of mononucleosomes. We further demonstrated that H3.3 actively marks enhancers and determines the transcriptional potential of retinoid acid (RA)-regulated genes via creating an open chromatin signature that enables the binding of RAR/RXR. Additionally, the H3.3-dependent recruitment of H2A.Z on promoter regions resulted in compaction of chromatin to poise transcription, while RA induction results in the incorporation of H3.3 on promoter regions to activate transcription via counteracting H2A.Z-mediated chromatin compaction. Our results provide key insights into the mechanism of how histone variants H3.3 and H2A.Z function together to regulate gene transcription via the modulation of chromatin dynamics over the enhancer and promoter regions.

Challenges for rotational grazing practice: Views from non-adopters across the Great Plains, USA.

Many ranchers who practice rotational grazing have experienced economic and ecological benefits. However, the adoption rate of rotational grazing has stagnated. To identify major challenges faced by non-adopters of rotational grazing as well as factors that affect the perceptions about different challenges, we conducted a mail survey of 4250 eligible ranchers in North Dakota, South Dakota and Texas, USA. Key categories of information obtained included basic ranch information, rotational grazing adoption status, and related information. Among 875 respondents, 40.4% identified themselves as non-adopters and perceived labor and water source constraints as the two major challenges, followed by high initial investment costs. This indicates the need for technical support and educational programs to address producers' concerns in addition to the monetary support from government subsidy programs. Findings from logistic regression analyses further indicate that landowners with higher quality soil, relatively more grassland (in both acres and percentage) and more owned land, generally perceive lower barriers to choosing rotational grazing practices and, therefore, may be a suitable target group for more effective outreach efforts and public fund investments to enhance the adoption of beneficial rotational grazing practices.

Novel Sulfolobus Virus with an Exceptional Capsid Architecture.

A novel archaeal virus, denoted Sulfolobus ellipsoid virus 1 (SEV1), was isolated from an acidic hot spring in Costa Rica. The morphologically unique virion of SEV1 contains a protein capsid with 16 regularly spaced striations and an 11-nm-thick envelope. The capsid exhibits an unusual architecture in which the viral DNA, probably in the form of a nucleoprotein filament, wraps around the longitudinal axis of the virion in a plane to form a multilayered disk-like structure with a central hole, and 16 of these structures are stacked to generate a spool-like capsid. SEV1 harbors a linear double-stranded DNA genome of ∼23 kb, which encodes 38 predicted open reading frames (ORFs). Among the few ORFs with a putative function is a gene encoding a protein-primed DNA polymerase. Sixfold symmetrical virus-associated pyramids (VAPs) appear on the surface of the SEV1-infected cells, which are ruptured to allow the formation of a hexagonal opening and subsequent release of the progeny virus particles. Notably, the SEV1 virions acquire the lipid membrane in the cytoplasm of the host cell. The lipid composition of the viral envelope correlates with that of the cell membrane. These results suggest the use of a unique mechanism by SEV1 in membrane biogenesis.IMPORTANCE Investigation of archaeal viruses has greatly expanded our knowledge of the virosphere and its role in the evolution of life. Here we show that Sulfolobus ellipsoid virus 1 (SEV1), an archaeal virus isolated from a hot spring in Costa Rica, exhibits a novel viral shape and an unusual capsid architecture. The SEV1 DNA wraps multiple times in a plane around the longitudinal axis of the virion to form a disk-like structure, and 16 of these structures are stacked to generate a spool-like capsid. The virus acquires its envelope intracellularly and exits the host cell by creating a hexagonal hole on the host cell surface. These results shed significant light on the diversity of viral morphogenesis.

Biodegradation of phthalic acid esters (PAEs) by Janthinobacterium sp. strain E1 under stress conditions.

Phthalates esters (PAEs) are a kind of polymeric material additives widely been added into plastics to improve products' flexibility. It can easily cause environmental pollution which are hazards to public health. In this study, we isolated an efficient PAEs degrading strain, Janthinobacterium sp. E1, and determined its degradation effect of di-2-ethylhexyl phthalate (DEHP) under stress conditions. Strain E1 showed an obvious advantage in pollutants degradation under various environmental stress conditions. Degradation halo clearly occurred around the colony of strain E1 on agar plate supplemented with triglyceride. Strain E1's esterase is a constitutively expressed intracellular enzyme. The esterase purified from strain E1 showed a higher catalytic effect on short-chain PAEs than long-chain PAEs. The input of DEHP, DBP (dibutyl phthalate) and DMP (dimethyl phthalate) into the tested soil did not change the species composition of soil prokaryotic community, but altered the dominant species in specific environmental conditions. And the community diversity and richness decreased to a certain extent. However, the diversity and richness of the microbial community were improved after the contaminated soil was treated with the strain E1. Our results also suggested that strain E1 exhibited a tremendous potential in environmental bioremediation in the real environment, which provides a new insight into the elimination of the pollutants contamination in the urban environment.

Emerging weed resistance increases tillage intensity and greenhouse gas emissions in the US corn-soybean cropping system.

Tillage is a common agricultural practice that helps prepare the soil and remove weeds. However, it remains unknown how tillage intensity has evolved and its effect on net greenhouse gas (GHG) emissions. Here, using a process-based modelling approach with a multi-source database, we examined the change in tillage intensity across the US corn-soybean cropping systems during 1998-2016 and the impact of tillage intensity on soil GHG emissions. We found that tillage intensity first decreased and then, after 2008, increased, a trend that is strongly correlated with the adoption of herbicide-tolerant crops and emerging weed resistance. The GHG mitigation benefit (-5.5 ± 4.8 TgCO2e yr-1) of decreasing tillage intensity before 2008 has been more than offset by increased GHG emissions (13.8 ± 5.6 TgCO2e yr-1) due to tillage reintensification under growing pressure of weed resistance. As weed resistance persists or grows, tillage intensity is anticipated to continue rising, probably increasing GHG emissions. Our results imply that farmers' choices in managing herbicide resistance may help mitigate agricultural GHG emissions, underscoring the importance of an alternative strategy to control weeds.

Least-cost control of agricultural nutrient contributions to the Gulf of Mexico hypoxic zone.

In 2008, the hypoxic zone in the Gulf of Mexico, measuring 20 720 km2, was one of the two largest reported since measurement of the zone began in 1985. The extent of the hypoxic zone is related to nitrogen and phosphorous loadings originating on agricultural fields in the upper Midwest. This study combines the tools of evolutionary computation with a water quality model and cost data to develop a trade-off frontier for the Upper Mississippi River Basin specifying the least cost of achieving nutrient reductions and the location of the agricultural conservation practices needed. The frontier allows policymakers and stakeholders to explicitly see the trade-offs between cost and nutrient reductions. For example, the cost of reducing annual nitrate-N loadings by 30% is estimated to be US$1.4 billion/year, with a concomitant 36% reduction in P and the cost of reducing annual P loadings by 30% is estimated to be US$370 million/year, with a concomitant 9% reduction in nitrate-N.

Ultrastretchable Liquid Metal Electrical Conductors Built-in Cloth Fiber Networks for Wearable Electronics.

Flexible, stretchable, and wearable electrically conductive elements were prepared by coating partially oxidized liquid metals (POLMs) on cloth material, i.e., nylon lycra fabric (NLF, see details in the Supporting Information), which were achieved by filling POLMs in fiber networks. The products show good and stable electrically conductive properties upon strong twisting and stretching. A wearable electrical heating function is then demonstrated as a direct application. The infrared thermal images of the POLM conducting wires indicate that the distribution of POLMs in NLF is uniform. Time-dependent heating temperature versus different stretching demonstrates that the POLMs/NLF heating element is highly reliable and endurable. Moreover, the electrical resistance remains unchanged after 1000 cycles of bending and twisting. These characterization methods prove that POLMs can be applied to clothes and enable ultrathin, comfortable electronic applications.

Generation of Functional Hepatocytes from Human Adipose-Derived MYC+ KLF4+ GMNN+ Stem Cells Analyzed by Single-Cell RNA-Seq Profiling.

Cell transplantation holds considerable promise for end-stage liver diseases but identifying a suitable, transplantable cell type has been problematic. Here, we describe a novel type of mesenchymal stem cells (MSCs) from human adipose tissue. These cells are different from previously reported MSCs, they are in the euchromatin state with epigenetic multipotency, and express pluripotent markers MYC, KLF4, and GMNN. Most of the genes associated with germ layer specification are modified by H3K4me3 or co-modified by H3K4me3 and H3K27me3. We named this new type of MSCs as adult multipotent adipose-derived stem cells (M-ADSCs). Using a four-step nonviral system, M-ADSCs can be efficiently Induced into hepatocyte like cells with expression of hepatocyte markers, drug metabolizing enzymes and transporters, and the other basic functional properties including albumin (ALB) secretion, glycogen storage, detoxification, low-density lipoprotein intake, and lipids accumulation. In vivo both M-ADSCs-derived hepatoblasts and hepatocytes could form vascularized liver-like tissue, secrete ALB and express metabolic enzymes. Single-cell RNA-seq was used to investigate the important stages in this conversion. M-ADSCs could be converted to a functionally multipotent state during the preinduction stage without undergoing reprogramming process. Our findings provide important insights into mechanisms underlying cell development and conversion. Stem Cells Translational Medicine 2018;7:792-805.

Analysis of chromatin fibers in Hela cells with electron tomography.

The presence and folding pattern of chromatin in eukaryotic cells remain elusive and controversial. In this study, we prepared ultra-thin sections of Hela cells with three different fixation and sectioning methods, i.e., chemical fixation, high pressure freezing with freeze substitution, and cryo-ultramicrotomy with SEM-FIB (focused ion beam), and analyzed in vivo architecture of chromatin fibers in Hela nuclei with electron tomography technology. The results suggest that the chromatin fibers in eukaryotic Hela cells are likely organized in an architecture with a diameter of about 30 nm.

Cryo-EM structure of isomeric molluscan hemocyanin triggered by viral infection.

Hemocyanins (Hcs) of arthropods and mollusks function not only as oxygen transporters, but also as phenoloxidases (POs). In invertebrates, PO is an important component in the innate immune cascade, where it functions as the initiator of melanin synthesis, a pigment involved in encapsulating and killing of pathogenic microbes. Although structures of Hc from several species of invertebrates have been reported, the structural basis for how PO activity is triggered by structural changes of Hc in vivo remains poorly understood. Here, we report a 6.8 Å cryo-electron microscopy (cryo-EM) structure of the isomeric form of hemocyanin, which was isolated from Abalone Shriveling syndrome-associated Virus (AbSV) infected abalone (Halitotis diversicolor), and build a pseudoatomic model of isomeric H. diversicolor hemocyanin 1 (HdH1). Our results show that, compared with native form of HdH1, the architecture of isomeric HdH1 turns into a more relaxed form. The interactions between certain functional units (FUs) present in the native form of Hc either decreased or were totally abolished in the isomeric form of Hc. As a result of that, native state Hc switches to its isomeric form, enabling it to play its role in innate immune responses against invading pathogens.