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The possibility of tailoring physical properties by changing the number of layers in van der Waals crystals is one of the driving forces behind the emergence of two-dimensional materials. One example is bulk MoS 2 , which changes from an indirect gap semiconductor to a direct bandgap semiconductor in the monolayer form. Here, we show a much bigger tuning range with a complete switching from a metal to a semiconductor in atomically thin PtSe 2 as its thickness is reduced. Crystals with a thickness of ~13 nm show metallic behavior with a contact resistance as low as 70 Ω·µm. As they are thinned down to 2.5 nm and below, we observe semiconducting behavior. In such thin crystals, we demonstrate ambipolar transport with a bandgap smaller than 2.2 eV and an on/off ratio of ~10 5 . Our results demonstrate that PtSe 2 possesses an unusual behavior among 2D materials, enabling novel applications in nano and optoelectronics. The electronic band structure of van der Waals crystals is strongly sensitive to the number of layers. Here, the authors observe a thickness-dependent metal-to-semiconductor transition in layered PtSe 2 by means of electrical transport measurements.

The interplay between band topology and magnetism can give rise to exotic states of matter. For example, magnetically doped topological insulators can realize a Chern insulator that exhibits quantized Hall resistance at zero magnetic field. While prior works have focused on ferromagnetic systems, little is known about band topology and its manipulation in antiferromagnets. Here, we report that MnBi 2 Te 4 is a rare platform for realizing a canted-antiferromagnetic (cAFM) Chern insulator with electrical control. We show that the Chern insulator state with Chern number C  = 1 appears as the AFM to canted-AFM phase transition happens. The Chern insulator state is further confirmed by observing the unusual transition of the C  = 1 state in the cAFM phase to the C  = 2 orbital quantum Hall states in the magnetic field induced ferromagnetic phase. Near the cAFM-AFM phase boundary, we show that the dissipationless chiral edge transport can be toggled on and off by applying an electric field alone. We attribute this switching effect to the electrical field tuning of the exchange gap alignment between the top and bottom surfaces. Our work paves the way for future studies on topological cAFM spintronics and facilitates the development of proof-of-concept Chern insulator devices. Exotic states emerge from the interplay between band topology and ferromagnetism, but it remains less known in canted-antiferromagnetic phase. Here, the authors realize a canted-antiferromagnetic Chern insulator in atomically-thin MnBi 2 Te 4 with electrical control of chiral-edge state transport.

An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in the same population. Application of these ideas to the study of early human embryonic development may reveal important insights into the transcriptional programs controlling this process, based on which components are most tightly regulated. Using a published single cell RNA-seq data set of human embryos collected at four-cell, eight-cell, morula and blastocyst stages, we identified genes with the most stable, invariant expression across all four developmental stages. Stably-expressed genes were found to be enriched for those sharing indispensable features, including essentiality, haploinsufficiency, and ubiquitous expression. The stable genes were less likely to be associated with loss-of-function variant genes or human recessive disease genes affected by a DNA copy number variant deletion, suggesting that stable genes have a functional impact on the regulation of some of the basic cellular processes. Genes with low expression variability at early stages of development are involved in regulation of DNA methylation, responses to hypoxia and telomerase activity, whereas by the blastocyst stage, low-variability genes are enriched for metabolic processes as well as telomerase signaling. Based on changes in expression variability, we identified a putative set of gene expression markers of morulae and blastocyst stages. Experimental validation of a blastocyst-expressed variability marker demonstrated that HDDC2 plays a role in the maintenance of pluripotency in human ES and iPS cells. Collectively our analyses identified new regulators involved in human embryonic development that would have otherwise been missed using methods that focus on assessment of the average expression levels; in doing so, we highlight the value of studying expression variability for single cell RNA-seq data.

With a view towards harnessing the therapeutic potential of canine mesenchymal stromal cells (cMSCs) as modulators of inflammation and the immune response, and to avoid the issues of the variable quality and quantity of harvested cMSCs, we examined the immunomodulatory properties of cMSCs derived from canine induced pluripotent stem cells (ciMSCs), and compared them to cMSCs harvested from adipose tissue (cAT-MSC) and bone marrow (cBM-MSC). A combination of deep sequencing and quantitative RT-PCR of the ciMSC transcriptome confirmed that ciMSCs express more genes in common with cBM-MSCs and cAT-MSCs than with the ciPSCs from which they were derived. Both ciMSCs and harvested cMSCs express a range of pluripotency factors in common with the ciPSCs including NANOG, POU5F1 (OCT-4), SOX-2, KLF-4, LIN-28A, MYC, LIF, LIFR , and TERT . However, ESRRB and PRDM-14 , both factors associated with naïve, rather than primed, pluripotency were expressed only in the ciPSCs. CXCR-4, which is essential for the homing of MSCs to sites of inflammation, is also detectable in ciMSCs, cAT- and cBM-MSCs, but not ciPSCs. ciMSCs constitutively express the immunomodulatory factors iNOS , GAL-9 , TGF-β1, PTGER-2α and VEGF , and the pro-inflammatory mediators COX-2, IL-1β and IL-8. When stimulated with the canine pro-inflammatory cytokines tumor necrosis factor-α (cTNF-α), interferon-γ (cIFN-γ), or a combination of both, ciMSCs upregulated their expression of IDO, iNOS , GAL-9, HGF, TGF-β1, PTGER-2α, VEGF, COX-2, IL-1β and IL-8. When co-cultured with mitogen-stimulated lymphocytes, ciMSCs downregulated their expression of iNOS , HGF , TGF-β1  and PTGER-2α, while increasing their expression of COX-2, IDO and IL-1β . Taken together, these findings suggest that ciMSCs possess similar immunomodulatory capabilities as harvested cMSCs and support further investigation into their potential use for the management of canine immune-mediated and inflammatory disorders.

A Chern insulator is a two-dimensional material that hosts chiral edge states produced by the combination of topology with time reversal symmetry breaking. Such edge states are perfect one-dimensional conductors, which may exist not only on sample edges, but on any boundary between two materials with distinct topological invariants (or Chern numbers). Engineering of such interfaces is highly desirable due to emerging opportunities of using topological edge states for energy-efficient information transmission. Here, we report a chiral edge-current divider based on Chern insulator junctions formed within the layered topological magnet MnBi 2 Te 4 . We find that in a device containing a boundary between regions of different thickness, topological domains with different Chern numbers can coexist. At the domain boundary, a Chern insulator junction forms, where we identify a chiral edge mode along the junction interface. We use this to construct topological circuits in which the chiral edge current can be split, rerouted, or switched off by controlling the Chern numbers of the individual domains. Our results demonstrate MnBi 2 Te 4 as an emerging platform for topological circuits design. Topological materials hold great promise for dissipationless information transmission. Here, the authors create Chern insulator junctions between domains with different Chern numbers in MnBi 2 Te 4 to realize the basic operation of a topological circuit.

Atomically thin rhenium disulphide (ReS 2 ) is a member of the transition metal dichalcogenide family of materials. This two-dimensional semiconductor is characterized by weak interlayer coupling and a distorted 1T structure, which leads to anisotropy in electrical and optical properties. Here we report on the electrical transport study of mono- and multilayer ReS 2 with polymer electrolyte gating. We find that the conductivity of monolayer ReS 2 is completely suppressed at high carrier densities, an unusual feature unique to monolayers, making ReS 2 the first example of such a material. Using dual-gated devices, we can distinguish the gate-induced doping from the electrostatic disorder induced by the polymer electrolyte itself. Theoretical calculations and a transport model indicate that the observed conductivity suppression can be explained by a combination of a narrow conduction band and Anderson localization due to electrolyte-induced disorder. Rhenium disulphide, ReS 2 , is a member of the two-dimensional dichalcogenide family. Here, the authors find a suppression of conductivity at high charge density levels in devices with polymer electrolyte gates. The effects of doping and disorder are explored theoretically and experimentally.

Previous studies have demonstrated the ability of bone morphogenetic proteins (BMPs) to promote chondrogenic differentiation in vitro. However, the in vivo role of BMP signaling during chondrogenesis has been unclear. We report here that BMP signaling is essential for multiple aspects of early chondrogenesis. Whereas mice deficient in type 1 receptors Bmpr1a or Bmpr1b in cartilage are able to form intact cartilaginous elements, double mutants develop a severe generalized chondrodysplasia. The majority of skeletal elements that form through endochondral ossification are absent, and the ones that form are rudimentary. The few cartilage condensations that form in double mutants are delayed in the prechondrocytic state and never form an organized growth plate. The reduced size of mutant condensations results from increased apoptosis and decreased proliferation. Moreover, the expression of cartilage-specific extracellular matrix proteins is severely reduced in mutant elements. We demonstrate that this defect in chondrocytic differentiation can be attributed to lack of Sox9, L-Sox5, and Sox6 expression in precartilaginous condensations in double mutants. In summary, our study demonstrates that BMPR1A and BMPR1B are functionally redundant during early chondrogenesis and that BMP signaling is required for chondrocyte proliferation, survival, and differentiation in vivo.

Background Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with a typical 5 year survival rate of <40 %. DNA methylation in tumour-suppressor genes often occurs at an early stage of tumorigenesis, hence DNA methylation can be used as an early tumour biomarker. Saliva is an ideal diagnostic medium to detect early HNSCC tumour activities due to its proximity to tumour site, non-invasiveness and ease of sampling. We test the hypothesis that the surveillance of DNA methylation in five tumour-suppressor genes ( RASSF1α , p16 INK4a , TIMP3 , PCQAP / MED15 ) will allow us to diagnose HNSCC patients from a normal healthy control group as well as to discriminate between Human Papillomavirus (HPV)-positive and HPV-negative patients. Methods Methylation-specific PCR (MSP) was used to determine the methylation levels of RASSF1α , p16 INK4a , TIMP3 and PCQAP / MED15 in DNA isolated from saliva. Statistical analysis was carried out using non-parametric Mann-Whitney’s U -test for individually methylated genes. A logistic regression analysis was carried out to determine the assay sensitivity when combing the five genes. Further, a five-fold cross-validation with a bootstrap procedure was carried out to determine how well the panel will perform in a real clinical scenario. Results Salivary DNA methylation levels were not affected by age. Salivary DNA methylation levels for RASSF1α , p16 INK4a , TIMP3 and PCQAP / MED15 were higher in HPV-negative HNSCC patients ( n  = 88) compared with a normal healthy control group ( n  = 122) (sensitivity of 71 % and specificity of 80 %). Conversely, DNA methylation levels for these genes were lower in HPV-positive HNSCC patients ( n  = 45) compared with a normal healthy control group (sensitivity of 80 % and specificity of 74 %), consistent with the proposed aetiology of HPV-positive HNSCCs. Conclusions Salivary DNA tumour-suppressor methylation gene panel has the potential to detect early-stage tumours in HPV-negative HNSCC patients. HPV infection was found to deregulate the methylation levels in HPV-positive HNSCC patients. Large-scale double-blinded clinical trials are crucial before this panel can potentially be integrated into a clinical setting.

We previously reported that synthetic vaccine particles (SVP) encapsulating antigens and TLR agonists resulted in augmentation of immune responses with minimal production of systemic inflammatory cytokines. Here we evaluated two different polymer formulations of SVP-encapsulated antigens and tested their ability to induce cytolytic T lymphocytes (CTL) in combination with SVP-encapsulated adjuvants. One formulation led to efficient antigen processing and cross-presentation, rapid and sustained CTL activity, and expansion of CD8+ T cell effector memory cells locally and centrally, which persisted for at least 1-2 years after a single immunization. SVP therapeutic dosing resulted in suppression of tumor growth and a substantial delay in mortality in several syngeneic mouse cancer models. Treatment with checkpoint inhibitors and/or cytotoxic drugs, while suboptimal on their own, showed considerable synergy with SVP immunization. SVP encapsulation of endosomal TLR agonists provided superior CTL induction, therapeutic benefit and/or improved safety profile compared to free adjuvants. SVP vaccines encapsulating mutated HPV-16 E7 and E6/E7 recombinant proteins led to induction of broad CTL activity and strong inhibition of TC-1 tumor growth, even when administered therapeutically 13-14 days after tumor inoculation in animals bearing palpable tumors. A pilot study in non-human primates showed that SVP-encapsulated E7/E6 adjuvanted with SVP-encapsulated poly(I:C) led to robust induction of antigen-specific T and B cell responses.

The ten mouse and six human members of the Schlafen (Slfn) gene family all contain an AAA domain. Little is known of their function, but previous studies suggest roles in immune cell development. In this report, we assessed Slfn regulation and function in macrophages, which are key cellular regulators of innate immunity. Multiple members of the Slfn family were up-regulated in mouse bone marrow-derived macrophages (BMM) by the Toll-like Receptor (TLR)4 agonist lipopolysaccharide (LPS), the TLR3 agonist Poly(I∶C), and in disease-affected joints in the collagen-induced model of rheumatoid arthritis. Of these, the most inducible was Slfn4. TLR agonists that signal exclusively through the MyD88 adaptor protein had more modest effects on Slfn4 mRNA levels, thus implicating MyD88-independent signalling and autocrine interferon (IFN)-β in inducible expression. This was supported by the substantial reduction in basal and LPS-induced Slfn4 mRNA expression in IFNAR-1⁻/⁻ BMM. LPS causes growth arrest in macrophages, and other Slfn family genes have been implicated in growth control. Slfn4 mRNA levels were repressed during macrophage colony-stimulating factor (CSF-1)-mediated differentiation of bone marrow progenitors into BMM. To determine the role of Slfn4 in vivo, we over-expressed the gene specifically in macrophages in mice using a csf1r promoter-driven binary expression system. Transgenic over-expression of Slfn4 in myeloid cells did not alter macrophage colony formation or proliferation in vitro. Monocyte numbers, as well as inflammatory macrophages recruited to the peritoneal cavity, were reduced in transgenic mice that specifically over-expressed Slfn4, while macrophage numbers and hematopoietic activity were increased in the livers and spleens. Slfn4 mRNA levels were up-regulated during macrophage activation but down-regulated during differentiation. Constitutive Slfn4 expression in the myeloid lineage in vivo perturbs myelopoiesis. We hypothesise that the down-regulation of Slfn4 gene expression during macrophage differentiation is a necessary step in development of this lineage.