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The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the epididymis. Males lacking Nicol are sterile due to impaired NELL2-mediated lumicrine signalling, leading to defective epididymal differentiation and deficient sperm maturation but can be restored by NICOL expression in testicular germ cells. Our results demonstrate how lumicrine signalling regulates epididymal function for successful sperm maturation and male fertility.

Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206+ M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206+ M2-like macrophages or deletion of CD206+ M2-like macrophages-specific TGF-β1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206+ M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206+ M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-β signaling. Here we show that CD206+ M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells.

Second-order nonlinear optical processes are used to convert light from one wavelength to another and to generate quantum entanglement. Creating chip-scale devices to more efficiently realize and control these interactions greatly increases the reach of photonics. Optical crystals and guided wave devices made from lithium niobate and potassium titanyl phosphate are typically used to realize second-order processes but face significant drawbacks in scalability, power, and tailorability when compared to emerging integrated photonic systems. Silicon or silicon nitride integrated photonic circuits enhance and control the third-order optical nonlinearity by confining light in dispersion-engineered waveguides and resonators. An analogous platform for second-order nonlinear optics remains an outstanding challenge in photonics. It would enable stronger interactions at lower power and reduce the number of competing nonlinear processes that emerge. Here we demonstrate efficient frequency doubling and parametric oscillation in a thin-film lithium niobate photonic circuit. Our device combines recent progress on periodically poled thin-film lithium niobate waveguidesand low-loss microresonators. Here we realize efficient >10% second-harmonic generation and parametric oscillation with microwatts of optical power using a periodically-poled thin-film lithium niobate microresonator. The operating regimes of this system are controlled using the relative detuning of the intracavity resonances. During nondegenerate oscillation, the emission wavelength is tuned over terahertz by varying the pump frequency by 100's of megahertz. We observe highly-enhanced effective third-order nonlinearities caused by cascaded second-order processes resulting in parametric oscillation. These resonant second-order nonlinear circuits will form a crucial part of the emerging nonlinear and quantum photonics platforms., 14 pages, 8 figures. Equal contribution by the first two authors

While aquatic (blue) and terrestrial (green) food webs are parts of the same landscape, it remains unclear whether they respond similarly to shared environmental gradients. We use empirical community data from hundreds of sites across Switzerland and a synthesis of interaction information in the form of a metaweb to show that inferred blue and green food webs have different structural and ecological properties along elevation and among various land-use types. Specifically, in green food webs, their modular structure increases with elevation and the overlap of consumers' diet niche decreases, while the opposite pattern is observed in blue food webs. Such differences between blue and green food webs are particularly pronounced in farmland-dominated habitats, indicating that anthropogenic habitat modification modulates the climatic effects on food webs but differently in blue versus green systems. These findings indicate general structural differences between blue and green food webs and suggest their potential divergent future alterations through land-use or climatic changes., Nature Communications, 13 (1), ISSN:2041-1723

Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA–DNA hybrid with a displaced non-template DNA strand. We developed RNA–DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA–DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41., Transcription can pose a threat to genomic instability through the formation of R-loops, which are RNA–DNA hybrids with a displaced non-template DNA strand. Here the authors mapped the R-loop proximal proteome in human cells and identified a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in gene promoters.

Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation., Building on the known role of BMP signalling in implantation, the authors define the role of uterine ACVR2A and ALK3 (via SMAD1/5) in vivo in regulating murine endometrial receptivity and embryo implantation.

The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. PKD2 mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD) and affect many cellular pathways. Data underlining the importance of ciliary PC2 localisation in preventing PKD are limited because PC2 function is ablated throughout the cell in existing model systems. Here, we dissect the ciliary role of PC2 by analysing mice carrying a non-ciliary localising, yet channel-functional, PC2 mutation. Mutants develop embryonic renal cysts that appear indistinguishable from mice completely lacking PC2. Despite not entering the cilium in mutant cells, mutant PC2 accumulates at the ciliary base, forming a ring pattern consistent with distal appendage localisation. This suggests a two-step model of ciliary entry; PC2 first traffics to the cilium base before TOP domain dependent entry. Our results suggest that PC2 localisation to the cilium is necessary to prevent PKD., The molecular role of ciliary Polycystin-2 (PC2) in cyst formation and polycystic kidney disease (ADKPD) is unclear. Here, the authors identify a PC2 mutant lacking ciliary localisation but with active Ca2+ channel function in mice, that is sufficient to generate an ADPKD phenotype.

Human land use may detrimentally affect biodiversity, yet long-term stability of species communities is vital for maintaining ecosystem functioning. Community stability can be achieved by higher species diversity (portfolio effect), higher asynchrony across species (insurance hypothesis) and higher abundance of populations. However, the relative importance of these stabilizing pathways and whether they interact with land use in real-world ecosystems is unknown. We monitored inter-annual fluctuations of 2,671 plant, arthropod, bird and bat species in 300 sites from three regions. Arthropods show 2.0-fold and birds 3.7-fold higher community fluctuations in grasslands than in forests, suggesting a negative impact of forest conversion. Land-use intensity in forests has a negative net impact on stability of bats and in grasslands on birds. Our findings demonstrate that asynchrony across species—much more than species diversity alone—is the main driver of variation in stability across sites and requires more attention in sustainable management., Long-term stability of ecological communities is vital for maintaining ecosystem functioning. Here, Blüthgen et al. show that greater land-use intensity in grasslands and forests can have negative impacts on the stability of plant and animal communities, driven primarily by variation in asynchrony between species.

Stabilization of covalent organic frameworks (COFs) by post-synthetic locking strategies is a powerful tool to push the limits of COF utilization, which are imposed by the reversible COF linkage. Here we introduce a sulfur-assisted chemical conversion of a two-dimensional imine-linked COF into a thiazole-linked COF, with full retention of crystallinity and porosity. This post-synthetic modification entails significantly enhanced chemical and electron beam stability, enabling investigation of the real framework structure at a high level of detail. An in-depth study by electron diffraction and transmission electron microscopy reveals a myriad of previously unknown or unverified structural features such as grain boundaries and edge dislocations, which are likely generic to the in-plane structure of 2D COFs. The visualization of such real structural features is key to understand, design and control structure–property relationships in COFs, which can have major implications for adsorption, catalytic, and transport properties of such crystalline porous polymers., Stabilization of covalent organic frameworks (COFs) by post-synthetic locking is a powerful tool to push the limits of COF utilization. Here the authors demonstrate a sulfur-assisted conversion of an imine-linked COF into a thiazole-linked COF, with retention of crystallinity and porosity, allowing for direct imaging of defects in COFs.

Understanding the unique mechanisms of human oogenesis necessitates the development of an in vitro system of stem cell differentiation into oocytes. Specialized cell types and organoids have been derived from human pluripotent stem cells in vitro, but generating a human ovarian follicle remains a challenge. Here we report that human embryonic stem cells can be induced to differentiate into ovarian follicle-like cells (FLCs) in vitro. First, we find that two RNA-binding proteins specifically expressed in germ cells, DAZL and BOULE, regulate the exit from pluripotency and entry into meiosis. By expressing DAZL and BOULE with recombinant human GDF9 and BMP15, these meiotic germ cells are further induced to form ovarian FLCs, including oocytes and granulosa cells. This robust in vitro differentiation system will allow the study of the unique molecular mechanisms underlying human pluripotent stem cell differentiation into late primordial germ cells, meiotic germ cells and ovarian follicles., In vitro production of human oocytes for the treatment of female infertility is a goal in reproductive medicine. Here, the authors establish in vitro conditions to generate human ovarian follicle-like cells from human embryonic stem cells.

Practical quantum communication between remote quantum memories rely on single photons at telecom wavelengths. Although spin-photon entanglement has been demonstrated in atomic and solid-state qubit systems, the produced single photons at short wavelengths and with polarization encoding are not suitable for long-distance communication, because they suffer from high propagation loss and depolarization in optical fibres. Establishing entanglement between remote quantum nodes would further require the photons generated from separate nodes to be indistinguishable. Here, we report the observation of correlations between a quantum-dot spin and a telecom single photon across a 2-km fibre channel based on time-bin encoding and background-free frequency downconversion. The downconverted photon at telecom wavelengths exhibits two-photon interference with another photon from an independent source, achieving a mean wavepacket overlap of greater than 0.89 despite their original wavelength mismatch (900 and 911 nm). The quantum-networking operations that we demonstrate will enable practical communication between solid-state spin qubits across long distances., Quantum communication requires quantum correlations between the information processing units and the information carrying units. Here, the authors use time-bin encoding and frequency downconversion to telecom wavelengths to achieve kilometre-scale spin-photon correlations.

Organogenesis of the ovary is a highly orchestrated process involving multiple lineage determination of ovarian surface epithelium, granulosa cells and theca cells. Although the sources of ovarian surface epithelium and granulosa cells are known, the origin(s) of theca progenitor cells have not been definitively identified. Here we show that theca cells derive from two sources: Wt1(+) cells indigenous to the ovary and Gli1(+) mesenchymal cells that migrate from the mesonephros. These progenitors acquire theca lineage marker Gli1 in response to paracrine signals Desert hedgehog (Dhh) and Indian hedgehog (Ihh) from granulosa cells. Ovaries lacking Dhh/Ihh exhibit theca layer loss, blunted steroid production, arrested folliculogenesis and failure to form corpora lutea. Production of Dhh/Ihh in granulosa cells requires growth differentiation factor 9 (GDF9) from the oocyte. Our studies provide the first genetic evidence for the origins of theca cells and reveal a multicellular interaction critical for the formation of a functional theca.

Upon congression at the spindle equator, vertebrate chromosomes display oscillatory movements which typically decline as cells progress towards anaphase. Kinesin-8 ​Kif18A has been identified as a suppressor of chromosome movements, but how its activity is temporally regulated to dampen chromosome oscillations before anaphase onset remained mysterious. Here, we identify a regulatory network composed of ​cyclin-dependent kinase-1 (​Cdk1) and protein phosphatase-1 (PP1) that antagonistically regulate ​Kif18A. ​Cdk1-mediated inhibitory phosphorylation of ​Kif18A promotes chromosome oscillations in early metaphase. PP1 induces metaphase plate thinning by directly dephosphorylating ​Kif18A. Chromosome attachment induces ​Cdk1 inactivation and kinetochore recruitment of ​PP1α/γ. Thus, we propose that chromosome biorientation mediates the alignment of chromosomes at the metaphase plate by tipping the balance in favour of dephosphorylated ​Kif18A capable of suppressing the oscillatory movements of chromosomes. Notably, interfering with chromosome oscillations severely impairs the fidelity of sister chromatid segregation demonstrating the importance of timely controlled chromosome dynamics for the maintenance of genome integrity.

Entanglement between stationary quantum memories and photonic qubits is crucial for future quantum communication networks. Although high-fidelity spin-photon entanglement was demonstrated in well-isolated atomic and ionic systems, in the solid-state, where massively parallel, scalable networks are most realistically conceivable, entanglement fidelities are typically limited due to intrinsic environmental interactions. Distilling high-fidelity entangled pairs from lower-fidelity precursors can act as a remedy, but the required overhead scales unfavourably with the initial entanglement fidelity. With spin-photon entanglement as a crucial building block for entangling quantum network nodes, obtaining high-fidelity entangled pairs becomes imperative for practical realization of such networks. Here we report the first results of complete state tomography of a solid-state spin-photon-polarization-entangled qubit pair, using a single electron-charged indium arsenide quantum dot. We demonstrate record-high fidelity in the solid-state of well over 90%, and the first (99.9%-confidence) achievement of a fidelity that will unambiguously allow for entanglement distribution in solid-state quantum repeater networks.

Photons are ideal carriers of quantum information, as they can be easily created and can travel long distances without being affected by decoherence. For this reason, they are well suited for quantum communication. However, the interaction between single photons is negligible under most circumstances. Realising such an interaction is not only fundamentally fascinating but holds great potential for emerging technologies. It has recently been shown that even weak optical nonlinearities between single photons can be used to perform important quantum communication tasks more efficiently than methods based on linear optics, which have fundamental limitations. Nonlinear optical effects at single photon levels in atomic media have been studied and demonstrated but these are neither flexible nor compatible with quantum communication as they impose restrictions on photons' wavelengths and bandwidths. Here we use a high efficiency nonlinear waveguide to observe the sum-frequency generation between a single photon and a single-photon level coherent state from two independent sources. The use of an integrated, room-temperature device and telecom wavelengths makes this approach to photon-photon interaction well adapted to long distance quantum communication, moving quantum nonlinear optics one step further towards complex quantum networks and future applications such as device independent quantum key distribution.

Citrobacter rodentium is a natural mouse pathogen widely used as a model for enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. While C. rodentium causes self-limiting colitis in most inbred mouse strains, it induces fatal diarrhoea in susceptible strains. The physiological pathways as well as the genetic determinants leading to susceptibility have remained largely uncharacterized. Here we use a forward genetic approach to identify the R-spondin2 gene as a major determinant of susceptibility to C. rodentium infection. Robust induction of R-spondin2 expression during infection in susceptible mouse strains causes a potent Wnt-mediated proliferative response of colonic crypt cells, leading to the generation of an immature and poorly differentiated colonic epithelium with deficiencies in ion-transport components. Our data demonstrate a previously unknown role of R-spondins and Wnt signalling in susceptibility to infectious diarrhoea and identify R-spondin2 as a key molecular link between infection and intestinal homoeostasis. © 2013 Macmillan Publishers Limited. All rights reserved.