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Recent advances in photonic integrated circuits have enabled a new generation of programmable Mach–Zehnder meshes (MZMs) realized by using cascaded Mach–Zehnder interferometers capable of universal linear-optical transformations on N input/output optical modes. MZMs serve critical functions in photonic quantum information processing, quantum-enhanced sensor networks, machine learning and other applications. However, MZM implementations reported to date rely on thermo-optic phase shifters, which limit applications due to slow response times and high power consumption. Here we introduce a large-scale MZM platform made in a 200 mm complementary metal–oxide–semiconductor foundry, which uses aluminium nitride piezo-optomechanical actuators coupled to silicon nitride waveguides, enabling low-loss propagation with phase modulation at greater than 100 MHz in the visible–near-infrared wavelengths. Moreover, the vanishingly low hold-power consumption of the piezo-actuators enables these photonic integrated circuits to operate at cryogenic temperatures, paving the way for a fully integrated device architecture for a range of quantum applications.A four-port programmable interferometer based on aluminium nitride piezo-optomechanical actuators coupled to silicon nitride waveguides is reported. Its low-power mechanism, which can be fabricated in a complementary metal–oxide–semiconductor foundry, facilitates operation at cryogenic temperatures.

Many proteins regulate the expression of genes by binding to specific regions encoded in the genome 1 . Here we introduce a new data set of RNA elements in the human genome that are recognized by RNA-binding proteins (RBPs), generated as part of the Encyclopedia of DNA Elements (ENCODE) project phase III. This class of regulatory elements functions only when transcribed into RNA, as they serve as the binding sites for RBPs that control post-transcriptional processes such as splicing, cleavage and polyadenylation, and the editing, localization, stability and translation of mRNAs. We describe the mapping and characterization of RNA elements recognized by a large collection of human RBPs in K562 and HepG2 cells. Integrative analyses using five assays identify RBP binding sites on RNA and chromatin in vivo, the in vitro binding preferences of RBPs, the function of RBP binding sites and the subcellular localization of RBPs, producing 1,223 replicated data sets for 356 RBPs. We describe the spectrum of RBP binding throughout the transcriptome and the connections between these interactions and various aspects of RNA biology, including RNA stability, splicing regulation and RNA localization. These data expand the catalogue of functional elements encoded in the human genome by the addition of a large set of elements that function at the RNA level by interacting with RBPs. A combination of five assays is used to produce a catalogue of RNA elements to which RNA-binding proteins bind in human cells.

Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low-grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid-derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity-associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity-associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC-driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity-related cancer.

Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transeriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles （〉2.3 billion paired reads）, we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed ＂mitotic trait＂ that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing 〉4 000 tumor samples in The Cancer Genome Atlas （TCGA） and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes.

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

Optical phase modulators operating at visible wavelengths are essential components for photonic technologies such as those for quantum control, communications, and laser ranging. However, they remain challenging to implement in scalable, integrated platforms capable of handling high optical powers. Here we present a visible-light, gigahertz-frequency acousto-optic phase modulator, fabricated on a 200-mm wafer in a volume CMOS foundry, that supports greater than 500 mW of optical power at 730 nm. The device combines a piezoelectric transducer and a photonic waveguide within a single, wavelength-scale structure that confines both a propagating optical mode and an electrically excitable breathing-mode mechanical resonance. By tuning the device's geometry to optimize the optomechanical interaction, we achieve modulation depths up to 4.85 rad with 80 mW of applied microwave power at 2.31 GHz in a 2-mm-long device. This corresponds to resonant modulation figures of merit of V = 1.32V and V  ⋅ L = 0.26V cm. To our knowledge, this is the lowest V ever demonstrated in any acousto-optic phase modulator and represents a 15-fold reduction in V and a 100-fold reduction in required microwave power relative to state-of-the-art modulators with high visible-wavelength power handling commonly employed in quantum control systems.

Web literacy refers to the skills and competencies people need in order to function in societies connected through the Internet. Many of the frameworks for understanding the components of web literacy are limited in value because they rely on conceptual definitions. They do not take into consideration the social practices governing the use and writing on the web. Nor do these frameworks take into account the open and participative nature of the Internet. With the aim of moving beyond this theoricist vision, we present an analysis of the relationship between the social practices of a group of university students in open learning environments and the acquisition of web skills. We proposed an alternative approach that is rooted in an understanding of social practices. In order to ＂operationalize＂ and facilitate an study of web skills, we relied on a specific type of analysis that allowed us to observe the consistency between the practices observed and the behavior reflected in the heuristic framework of web skills. The main elements of this alternative framework are explained, as is the link between the social practices of the students and the skills acquired. We also discuss other contributions to the field of Web Literacy and to the even larger field of Digital Literacy.

The addition of active, nonlinear, and nonreciprocal functionalities to passive piezoelectric acoustic wave technologies could enable all-acoustic and therefore ultra-compact radiofrequency signal processors. Toward this goal, we present a heterogeneously integrated acoustoelectric material platform consisting of a 50 nm indium gallium arsenide epitaxial semiconductor film in direct contact with a 41° YX lithium niobate piezoelectric substrate. We then demonstrate three of the main components of an all-acoustic radiofrequency signal processor: passive delay line filters, amplifiers, and circulators. Heterogeneous integration allows for simultaneous, independent optimization of the piezoelectric-acoustic and electronic properties, leading to the highest performing surface acoustic wave amplifiers ever developed in terms of gain per unit length and DC power dissipation, as well as the first-ever demonstrated acoustoelectric circulator with an isolation of 46 dB with a pulsed DC bias. Finally, we describe how the remaining components of an all-acoustic radiofrequency signal processor are an extension of this work. Radio frequency signal processing (RFSP) currently involves a mix of components with differing operation principles, which hinders miniaturisation. Here, Hackett et al. succeed in creating acoustic non-reciprocal circulators, amplifiers, and passive filters, paving the way for all acoustic single-chip RFSP.

Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control. Mitosis is a key step in the normal life cycle of a cell, during which one cell divides into two new cells. As a cell progresses through the cell cycle, it must carefully regulate its gene activity to switch particular genes on or off at specific moments. When a gene is activated its sequence is first copied into a temporary molecule called a transcript. These transcripts are then edited to form templates to build proteins. One way that a transcript can be edited is via a process called alternative splicing, in which different pieces of the transcript are cut and pasted together to form different versions of the final template. This allows different instructions to be obtained from a single gene, introducing an added layer of biological complexity. However, the role of alternative splicing in the timing of key events of the cell life cycle is not well understood. Dominguez et al. have now looked for the genes that undergo alternative splicing during the cell cycle. The sequences of gene transcripts produced within human cells were collected while the cells went through two rounds of division. This approach revealed that around 1,300 genes are spliced in different ways at different stages of each cell cycle. Many of these genes were known to play roles in controlling the cell’s life cycle, but few of the genes showed large changes in the amount of total transcript that is generated over time. Dominguez et al. also showed that an enzyme called CLK1 influences about half of the 1,300 periodically spliced genes during the cell cycle. The production of CLK1 is itself carefully controlled throughout the cell cycle, and the enzyme’s activity prevents its own overproduction. Further experiments showed that blocking CLK1’s activity while a cell is replicating its DNA halts the cell cycle, but blocking this enzyme’s activity after the cell had replicated its DNA did not. Given this pivotal role in the cell cycle, Dominguez et al. also examined the role of CLK1 in cancer cells and found that high levels of CLK1 in tumours were linked to lower survival rates. These findings indicate that CLK1 warrants further investigation, particularly in relation to its role in cancer.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP–effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of ‘dual-purpose’ peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP–effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP–effector interface. How RNA-binding proteins (RBPs) regulate gene expression via effectors of RNA processing is unclear. Here, the authors dissect the effector interface of an essential RBP, Unkempt, and investigate its contribution to translational control in cells.