Rational design of oral drugs targeting mucosa delivery with gut organoid platforms

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nanocarriers(NCs:silica nanospheres and gold nanocages)with poly-l-lysine(PLL)coating and mammalian orthoreovirus cell attachment proteinσ1 functionalization(NC-PLL-σ1)were explored as functional oral drug delivery vehicles(ODDVs).The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells(M-cells)mediated transcytosis(viaσ1-α2–3-linked sialic acids adherence)across gastrointestinal epithelia.PLL coating provided protection and slow-release of rhodamine 6 G(R6G),a model payload.The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro.When compared with other experimental groups,the fully functionalized ODDV system(with PLL-σ1)demonstrated two significant advantages:a significantly higher transport efficiency(198%over blank control at 48 h);and protection of payloads which led to both better transport efficiency and extended-release of payloads(61%over uncoated carriers at 48 h).In addition,it was shown that the M cell presence in intestinal organoid monolayers(modulated by Rank L stimulation)was a determining factor on the transport efficiency of the ODDVs:more M-cells(induced by higher Rank L)in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload(R6G).The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

RNA biology and therapeutics

Eukaryotic genomes undergo pervasive transcription,generating vast amounts of noncoding RNAs alongside protein-coding mRNAs[1].These noncoding RNAs,including small noncoding RNAs,long noncoding RNAs(lncRNAs),and circular RNAs,have been shown to play critical roles in gene regulation,chromatin remodeling,assembly of membraneless organelles,and other essential biological processes.They function through a diverse range of mechanisms[2],[3],[4],[5].Dysregulation of noncoding RNAs contributes to human disease pathogenesis and affects plant development and stress response[6],[7],[8].Over the past decade,significant progress has been made in unraveling the functions of noncoding RNAs and elucidating the molecular mechanisms by which they operate.The involvement of noncoding RNAs in human disease pathogenesis and agronomic trait regulation has garnered increasing attention.

Regulation of Rice Tillering by RNA-Directed DNA Methylation at Miniature Inverted-Repeat Transposable Elements

Tillering is a major determinant of rice plant architecture and grain yield.Here,we report that depletion of rice OsNRPD1a and OsNRPD1b,two orthologs of the largest subunit of RNA polymerase IV,leads to a high-tillering phenotype,in addition to dwarfism and smaller panicles.OsNRPD1a and OsNRPD1b are required for the production of 24-nt small interfering RNAs that direct DNA methylation at transposable elements(TEs)including miniature inverted-repeat TEs(MITEs).Interestingly,many genes are regulated either positively or negatively by TE methylation.Among them,OsMIR156d and OsMIR156j,which promote rice tillering,are repressed by CHH methylation at two MITEs in the promoters.By contrast,D14,which suppresses rice tillering,is activated by CHH methylation at an MITE in its downstream.Our findings reveal regulation of rice tillering by RNA-directed DNA methylation at MITEs and provide potential targets for agronomic trait enhancement through epigenome editing.

A Global Identification and Analysis of Small Nucleolar RNAs and Possible Intermediate-Sized Non-Coding RNAs in Oryza sativa

Accumulating evidence suggests that non-coding RNAs （ncRNAs） are both widespread and functionally important in many eukaryotic organisms. In this study, we employed a special size fractionation and cDNA library construction method followed by 454 deep sequencing to systematically profile rice intermediate-size ncRNAs. Our analysis resulted in the identification of 1349 ncRNAs in total, including 754 novel ncRNAs of an unknown functional category. Chromosome distribution of all identified ncRNAs showed no strand bias, and displayed a pattern similar to that observed in protein-coding genes with few chromosome dependencies. More than half of the ncRNAs were centered around the plus-strand of the 5＇ and 3＇ termini of the coding regions. The majority of the novel ncRNAs were rice specific, while 78% of the small nucleolar RNAs （snoRNAs） were conserved. Tandem duplication drove the expansion of over half of the snoRNA gene families. Furthermore, 90% of the snoRNA candidates were shown to produce small RNAs between 20-30 nt, 80% of which were associated with ARGONAUT proteins generally, and AGOlb in particular. Overall, our findings provide a comprehensive view of an intermediate-size non-coding transcriptome in a monocot species, which will serve as a useful platform for an in-depth analysis of ncRNA functions.

A 5′tRNA-Ala-derived small RNA regulates anti-fungal defense in plants

Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed Rtc B ligation-based small RNA(s RNA)sequencing,a method that captures and distinguishes between 3′-2′,3′-cyclic-phosphate(c P)/phosphate(P)-terminated s RNAs and 3′-OH-terminated s RNAs,and profiled 5′ts RNAs and 5′t RNA halves in Arabidopsis thaliana.We found that Arabidopsis 5′ts RNAs and 5′t RNA halves predominantly contain a c P at the 3′end and require S-like RNase 1(RNS1)and RNS3 for their production.One of the most abundant 5′ts RNAs,5′ts R-Ala,by associating with AGO1,negatively regulates Cytochrome P45071 A13(CYP71 A13)expression and camalexin biosynthesis to repress anti-fungal defense.Interestingly,5′ts R-Ala is downregulated upon fungal infection.Our study provides a global view of 5′ts RNAs and 5′t RNA halves in Arabidopsis and unravels an important role of a 5′ts RNA in regulating anti-fungal defense.

An expression atlas of miRNAs in Arabidopsis thaliana

MicroRNAs(miRNAs) are small non-coding RNAs that regulate a variety of biological processes. miRNA expression often exhibits spatial and temporal specificity. However, genome-wide miRNA expression patterns in different organs during development of Arabidopsis thaliana have not yet been systemically investigated. In this study, we sequenced small RNA libraries generated from 27 different organ/tissue types, which cover the entire life cycle of Arabidopsis. Analysis of the sequencing data revealed that most miRNAs are ubiquitously expressed, whereas a small set of miRNAs display highly specific expression patterns. In addition, different miRNA members within the same family have distinct spatial and temporal expression patterns. Moreover, we found that some miRNAs are produced from different arms of their hairpin precursors at different developmental stages. This work provides new insights into the regulation of miRNA biogenesis and a rich resource for future investigation of miRNA functions in Arabidopsis.

Image magnified lensless holographic projection by convergent spherical beam illumination

In liquid crystal spatial light modulator（SLM）-based holographic projection, the image is usually displayed at a distant projection screen through free space diffraction from a computer-generated hologram（CGH）. Therefore,it allows for removing of the projection lens for the sake of system simplification and being aberration free, known as the ＂lensless holographic projection＂. However, the maximum size of the optical projected image is limited by the diffraction angle of the SLM. In this Letter, we present a method for the implementation of image magnification in a lensless holographic projection system by using convergent spherical wave illumination to the SLM.The complete complex amplitude of the image wavefront is reconstructed in a lensless optical filtering system from a phase-only CGH that is encoded by the off-axis double-phase method. The dimensions of the magnified image can break the limitation by the maximum diffraction angle of the SLM at a given projection distance.Optical experiment results with successful image magnification in the lensless holographic projection system are presented.

Evolution of lmiRNAs and their targets from MITEs for rice adaptation

Twenty-four nucleotide long microRNAs(ImiRNAs)direct DNA methylation at target genes and regulate their transcription.The evolutionary origin of ImiRNAs and the range of ImiRNA-mediated regulation remain obscure.Here,we reannotated ImiRNAs and their targets in rice by applying stringent criteria.We found that the majority of ImiRNAs are derived from Miniature Inverted-repeat Transposable Elements(MITEs)and most sites targeted by MITE-derived ImiRNAs reside within MITEs,suggesting co-evolution of ImiRNAs and their targets through MITE amplification.ImiRNAs undergo dynamically changes under stress conditions and the genes targeted by ImiRNAs show an enrichment for stress-responsive genes,suggesting that ImiRNAs are widely involved in plant responses to stresses.We constructed the evolutionary histories of ImiRNAs and their targets.Nearly half of ImiRNAs emerged before or when the AA genome was diverged,while the emergence of ImiRNA targets coincided with or followed the emergence of ImiRNAs.Furthermore,we found that the sequences of a ImiRNA target site underwent variations,coincident with the divergence of rice accessions and the distribution of rice accessions in different geographical locations and climatic conditions.Our findings highlight MITEs as an important origin of ImiRNAs and suggest that the evolution of ImiRNA-target regulatory modules may contribute to rice adaptation to environmental changes.

Is oral microbiome of children able to maintain resistance and functional stability in response to short-term interference of ingesta?

Dear Editor,A series of studies had focused on the ecological stability of human microbiome(Lozupone et al.,2012;Faith et al.,2013;Moya and Ferrer,2016).Despite the continuous perturbation and the highly personalized composition within the human microbiome(Human Microbiome Project,2012),healthy adults stably maintain their microbial communities in terms of space and time(Faith et al.,2013;Moya and Ferrer,2016;Oh et al.,2016).This stability is proved to be critical for the well-being of human body(Lozupone et al.,2012).On the contrary,major shifts in microbial community composition are often related to diseases(Lynch and Pedersen,2016).

Plant non-coding RNAs and epigenetics

Epigenetics plays a large role in various aspects of plant biology,including development,response to biotic and abiotic stresses,silencing of transposable elements,and maintenance of genome stability.In plants,epigenetic regulation involves histone and DNA modifications and noncoding RNAs including small RNAs（s RNAs）and long noncoding RNAs（lnc RNAs）.This issue of Science China Life Sciences includes five review articles and eight research

Inhibitory activity of Bifidobacterium adolescent combined with cisplatin on melanoma in mice and its mechanism

The aim of this study is to explore inhibitory activity of Bifidobacterium adolescent combined with cis-platin on the growth of melanoma(B16)in mice and the underlying mechanism.C57 mice were inoculated with B16 cancer cells to construct mouse model of melanoma and treated with bifidobacterium adolescent combined with cisplatin.Ratios of inhibitory activity on the growth of melanoma(B16)were calculated.Pathology changes of the tumor were observed by HE staining.B16 cell cycles were examined on a flow cytometer.Lymphocyte prolif-eration was measured with MTT assay and the T-cell sub-set was measured by double marked fluorescence.When bifidobacterium of 1010 cfu/L was injected,the ratio of inhibitory activity on the growth of melanoma(B16)reached 54%,which was similar to that of cisplatin group.The ratio of inhibitory activity reached 74.45%when the mice were treated by bifidobacterium combined with cis-platin.HE staining shows that bifidobacterium inhibited B16 cell proliferation and enhanced the cisplatin`s killing activity on B16 cells.The results of flow cytometry demonstrated that B16 cell proliferation was arrested at G1 stage after treatment with bifidobacterium.The B16 cell proliferation was arrested at S stage after treatment with cisplatin.The CD4+percentage increased and the difference was significant compared with the normal group after treatment with bifidobacterium,indicating that T-cell immune activity was enhanced.Treatment with bifidobacterium combined with cisplatin can enhance the inhibitory activity on the growth of melanoma(B16)of cisplatin.The mechanism of the inhibitory activity on B16 cell proliferation is correlated with the enhanced immune activity in mice.

In memory of Professor Biao Ding(1960–2015)

It is with profound sadness that we mourn the loss of Dr. Biao Ding, a full-professor in the Department of Molecular Genetics, Ohio State University （OSU）, and a world-renowned plant biologist with leading authority in viroid research. He died suddenly on June 26, 2015 in Prague, Czech Republic, while attending the international Conference on Viroids and Viroid-Like RNAs as a Keynote Speaker. Dr. Ding was born in 196., in Kunming, Yunnan Province, China. He received his B.S. from Beijing Forestry University in 1982, and was then selected as one of the first group of outstanding young students to study abroad since the imolementation of China＇s Reform and Open Policy.

Special Issue on Plant Epigenetics

Epigenetics refers to gene regulation at the chromatin level. This can occur via modification of the DNA and the core proteins of the chromatin, histones （Liu et al., 2014）. In this issue, Reyes （2014） reviews recent advances in the roles of ATP-dependent chromatin-remodeling complexes on devel- opment, phytohormone response, and RNA-mediated silenc- ing and Da Ines et al. （2014） report the role of chromatin remodeling in homologous chromosome pairing. In addition, Over and Michaels （2014） discuss the emergent roles of plant histone linker proteins in gene regulation, cell division, and development.