Highlights d We build the genomic and transcriptomic landscape of 465 primary TNBCs d Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype d Transcriptomic data classify TNBCs into four subtypes d Multi-omics profiling identifies potential targets within specific TNBC subtypes

Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.

Determining the extent of adaptive evolution at the genomic level is central to our understanding of molecular evolution. A suitable observation for this purpose would consist of polymorphic data on a large and unbiased collection of genes from two closely related species, each having a large and stable population. In this study, we sequenced 419 genes from 24 lines of Drosophila melanogaster and its close relatives. Together with data from Drosophila simulans, these data reveal the following. (i) Approximately 10% of the loci in regions of normal recombination are much less polymorphic at silent sites than expected, hinting at the action of selective sweeps.(ii) The level of polymorphism is negatively correlated with the rate of nonsynonymous divergence across loci. Thus, even under strict neutrality, the ratio of amino acid to silent nucleotide changes (A:S) between Drosophila species is expected to be 25-40% higher than the A:S ratio for polymorphism when data are pooled across the genome. (iii) The observed A/S ratio between species among the 419 loci is 28.9% higher than the (adjusted) neutral expectation. We estimate that nearly 30% of the amino acid substitutions between D. melanogaster and its close relatives were adaptive. (iv) This signature of adaptive evolution is observable only in regions of normal recombination. Hence, the low level of polymorphism observed in regions of reduced recombination may not be driven primarily by positive selection. Finally, we discuss the theories and data pertaining to the interpretation of adaptive evolution in genomic studies.McDonald-Kreitman test ͉ selection ͉ polymorphism R ecent studies based on DNA sequence data from large numbers of genes have increasingly suggested the prevalence of adaptive evolution in coding (1-5) as well as noncoding (6, 7) regions. The extent to which positive selection influences DNA polymorphism and divergence appears to be incompatible with the Neutral Theory of Molecular Evolution (8). This theory posits that the overall pattern of DNA evolution can be accounted for by mutation, genetic drift, and negative selection. It does not deny the operation of positive selection on some loci but only asserts that the overall pattern of genomic evolution can be explained without invoking adaptive evolution. Presumably, adaptive changes at any given time involve too small a fraction of the genome to be a statistically significant factor, despite their overwhelming biological significance.The evidence used to test the Neutral Theory can be classified as divergence among species (9-11), polymorphism within species (12-14) or a combination of these (15, 16). The combined approach, as exemplified by the McDonald-Kreitman (MK) test and its derivatives, can separate the effects of negative and positive selection and is especially informative about adaptive evolution. Many such studies have concluded that positive selection may play a significant role in driving amino acid substitutions in the human and Drosophila melanogaster lineages (1-5).However, as...

A simple one-pot solvothermal method is reported to synthesize VS nanosheets featuring rich defects and an expanded (001) interlayer spacing as large as 1.00 nm, which is a ≈74% expansion as relative to that (0.575 nm) of the pristine counterpart. The interlayer-expanded VS nanosheets show extraordinary kinetic metrics for electrocatalytic hydrogen evolution reaction (HER), exhibiting a low overpotential of 43 mV at a geometric current density of 10 mA cm , a small Tafel slope of 36 mV dec , and long-term stability of 60 h without any current fading. The performance is much better than that of the pristine VS with a normal interlayer spacing, and even comparable to that of the commercial Pt/C electrocatalyst. The outstanding electrocatalytic activity is attributed to the expanded interlayer distance and the generated rich defects. Increased numbers of exposed active sites and modified electronic structures are achieved, resulting in an optimal free energy of hydrogen adsorption (∆G ) from density functional theory calculations. This work opens up a new door for developing transition-metal dichalcogenide nanosheets as high active HER electrocatalysts by interlayer and defect engineering.

In present work, a superlubricity phenomenon of phosphoric acid (H(3)PO(4)) was found under ambient conditions. An ultralow friction coefficient of about 0.004 between glass/Si(3)N(4) and sapphire/sapphire tribopairs was obtained under the lubrication of a phosphoric acid aqueous solution (pH 1.5) at high contact pressure (the maximum pressure can reach about 1.65 GPa) after a running-in period of about 600 s. The experimental results indicate that the superlow friction state was very stable for more than 3 h. In such a state, solidlike films formed on the two sliding surfaces, which are hydrates of phosphoric acid with a hydrogen-bonded network according to the Raman spectrum. The superlubricity mechanism is mainly attributed to the hydrogen bond effect that forms a hydrated water layer with low shearing strength, and the dipole-dipole effects that form an interfacial Coulomb repulsion force also make some contributions to low friction. This work may help us to introduce a new approach to superlubricity and may lead to the wide application of superlubricity in future technological and biomedical areas.

Cubic inorganic perovskite CsPbI 3 is a direct bandgap semiconductor, which is promising for optoelectronic applications, such as solar cells, light emitting diodes, and lasers. The intrinsic defects in semiconductors play crucial roles in determining carrier conductivity, the efficiency of carrier recombination, and so on. However, the thermodynamic stability and intrinsic defect physics are still unclear for cubic CsPbI 3 . By using the first-principles calculations, we study the thermodynamic process and find out that the window for CsPbI 3 growth is quite narrow and the concentration of Cs is important for cubic CsPbI 3 growth. Under Pb-rich conditions, V Pb and V I can pin the Fermi energy in the middle of the bandgap, which results in a low carrier concentration. Under Pb-poor conditions, V Pb is the dominant defect and the material has a high concentration of hole carriers with a long lifetime. Our present work gives an insight view of the defect physics of cubic CsPbI 3 and will be beneficial for optoelectronic applications based on cubic CsPbI 3 and other analogous inorganic perovskites.

Superlubricity of graphite and graphene has aroused increasing interest in recent years. Yet how to obtain a long-lasting superlubricity between graphene layers, under high applied normal load in ambient atmosphere still remains a challenge but is highly desirable. Here, we report a direct measurement of sliding friction between graphene and graphene, and graphene and hexagonal boron nitride (h-BN) under high contact pressures by employing graphene-coated microsphere (GMS) probe prepared by metal-catalyst-free chemical vapour deposition. The exceptionally low and robust friction coefficient of 0.003 is accomplished under local asperity contact pressure up to 1 GPa, at arbitrary relative surface rotation angles, which is insensitive to relative humidity up to 51% RH. This ultralow friction is attributed to the sustainable overall incommensurability due to the multi-asperity contact covered with randomly oriented graphene nanograins. This realization of microscale superlubricity can be extended to the sliding between a variety of two-dimensional (2D) layers.

Hydrogenated amorphous carbon (a-C:H) is capable of providing a near-frictionless lubrication state when rubbed in dry sliding contacts. Nevertheless, the mechanisms governing superlubricity in a-C:H are still not well comprehended, mainly due to the lack of spatially resolved structural information of the buried contact surface. Here, we present structural analysis of the carbonaceous sliding interfaces at the atomic scale in two superlubricious solid lubricants, a-C:H and Si-doped a-C:H (a-C:H:Si), by probing the contact area using state-of-the-art scanning electron transmission microscopy and electron energy-loss spectroscopy. The results emphasize the diversity of superlubricity mechanisms in a-C:Hs. They suggest that the occurrence of a superlubricious state is generally dependent on the formation of interfacial nanostructures, mainly a tribolayer, by different carbon rehybridization pathways. The evolution of such anti-friction nanostructures highly depends on the contact mechanics and the counterpart material. These findings enable a more effective manipulation of superlubricity and developments of new carbon lubricants with robust lubrication properties.