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Deep-learning language models have shown promise in various biotechnological applications, including protein design and engineering. Here we describe ProGen, a language model that can generate protein sequences with a predictable function across large protein families, akin to generating grammatically and semantically correct natural language sentences on diverse topics. The model was trained on 280 million protein sequences from >19,000 families and is augmented with control tags specifying protein properties. ProGen can be further fine-tuned to curated sequences and tags to improve controllable generation performance of proteins from families with sufficient homologous samples. Artificial proteins fine-tuned to five distinct lysozyme families showed similar catalytic efficiencies as natural lysozymes, with sequence identity to natural proteins as low as 31.4%. ProGen is readily adapted to diverse protein families, as we demonstrate with chorismate mutase and malate dehydrogenase. A generative deep-learning model designs artificial proteins with desired enzymatic activities.

Capillary condensation of water is ubiquitous in nature and technology. It routinely occurs in granular and porous media, can strongly alter such properties as adhesion, lubrication, friction and corrosion, and is important in many processes used by microelectronics, pharmaceutical, food and other industries 1 – 4 . The century-old Kelvin equation 5 is frequently used to describe condensation phenomena and has been shown to hold well for liquid menisci with diameters as small as several nanometres 1 – 4 , 6 – 14 . For even smaller capillaries that are involved in condensation under ambient humidity and so of particular practical interest, the Kelvin equation is expected to break down because the required confinement becomes comparable to the size of water molecules 1 – 22 . Here we use van der Waals assembly of two-dimensional crystals to create atomic-scale capillaries and study condensation within them. Our smallest capillaries are less than four ångströms in height and can accommodate just a monolayer of water. Surprisingly, even at this scale, we find that the macroscopic Kelvin equation using the characteristics of bulk water describes the condensation transition accurately in strongly hydrophilic (mica) capillaries and remains qualitatively valid for weakly hydrophilic (graphite) ones. We show that this agreement is fortuitous and can be attributed to elastic deformation of capillary walls 23 – 25 , which suppresses the giant oscillatory behaviour expected from the commensurability between the atomic-scale capillaries and water molecules 20 , 21 . Our work provides a basis for an improved understanding of capillary effects at the smallest scale possible, which is important in many realistic situations. In the tiniest of capillaries, barely larger than a water molecule, condensation is surprisingly predictable from the macroscopic Kelvin condensation equation, a coincidence partially owing to elastic deformation of the capillary walls.

A subunit of the ARC/Mediator co-activator complex is a key effector of the SREBP transcription factor during regulation of lipid homeostasis in human cells and Caenorhabditis elegans. The SREBP activation domain directly targets a KIX domain on ARC105/MED15 The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis 1 , 2 . We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms 3 , 4 , 5 . Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes 6 , 7 . We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15 , including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

Prostate cancer cells escape growth inhibition from transforming growth factor β (TGFβ) by downregulating TGFβ receptors. However, the mechanism by which cancer cells downregulate TGFβ receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling had a critical role in inhibiting TGFβ receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 3′-UTR and AR signaling further potentiates this effect in both untransformed and transformed human prostate epithelial cells as well as in human prostate cancers. Analysis of primary prostate cancers showed that increased miR-21/AR expression parallel a significantly reduced expression of TGFBR2. Manipulation of androgen signaling or the expression levels of AR or miR-21 negatively altered TGFBR2 expression in untransformed and transformed human prostate epithelial cells, human prostate cancer xenografts and mouse prostate glands. Importantly, we demonstrated that miR-21 and AR regulated each other’s expression resulting in a positive feedback loop. Our results indicated that miR-21/AR mediate its tumor-promoting function by attenuating TGFβ-mediated Smad2/3 activation, cell growth inhibition, cell migration and apoptosis. Together, these results suggest that the AR and miR-21 axis exerts its oncogenic effects in prostate tumors by downregulating TGFBR2, hence inhibiting the tumor-suppressive activity of TGFβ pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFβ in prostate cancer.

Particles directly produced at electron–positron colliders, such as the J/ψ meson, decay with relatively high probability into a baryon–antibaryon pair1. For spin-1/2 baryons, the pair can have the same or opposite helicites. A non-vanishing phase ΔΦ between the transition amplitudes to these helicity states results in a transverse polarization of the baryons2–4. From the joint angular distribution of the decay products of the baryons, this phase as well as the parameters characterizing the baryon and the antibaryon decays can be determined. Here, we report the measurement of ΔΦ = 42.4 ± 0.6 ± 0.5° using Λ → pπ− and Λ¯→p¯π+,n¯π0 decays at BESIII. We find a value for the Λ → pπ− decay parameter of α− = 0.750 ± 0.009 ± 0.004, 17 ± 3% higher than the current world average, which has been used as input for all Λ polarization measurements since 19785,6. For Λ¯→p¯π+ we find α+ = −0.758 ± 0.010 ± 0.007, giving ACP = (α− + α+)/(α− − α+) = −0.006 ± 0.012 ± 0.007, a precise direct test of charge–parity symmetry (CP) violation in Λ decays.The decay asymmetry and helicity phase of polarized baryon–antibaryon pairs are measured at the BESIII experiment, testing charge–parity symmetry and revealing a discrepancy of the Λ → pπ− decay asymmetry with respect to the current world average.

Sharp faceted interfaces are often observed between compound precipitates and matrix phases, which are remarkably different in their lattice parameters. Multiple orientation relationships (ORs) corresponding to various faceted interfaces tend to coexist in one alloy. A near row matching (NRM) approach is proposed for a systematic investigation of ORs corresponding to potential preferred interfaces. Unlike a common practice to search for misorientations corresponding to low sigma grain boundaries associated with matching periodicity in three dimensions (3D), this approach directly searches for ORs that permit local 2D periodic good matching structures in preferred interfaces. The calculation method consists of two simple steps to evaluate matching within and between rows of lattice points. The method has been applied to a Mg 2 Sn/Mg system. Ten of the forty-four predicted facets agree with the experimental observations, for the cases that the preferred facets can be described (approximately) by low index planes of the precipitates. The predictions can cover all known observations, if limited high index planes are included as candidates. Each observed facet is characterized with a periodic pattern of good matching sites (GMSs) in localized regions. NRM is a necessary condition for the existence of a periodic GMS pattern. The agreement between the calculation results and experimental results confirms the important role of periodic matching in the development of preferred interfaces and their corresponding ORs. It also demonstrates the usefulness of geometric matching study for quantitative predictions of potential preferred interfaces.

The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the transforming growth factor-β and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor ( Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion, and is associated with an increased number of putative cancer stem cells. In addition, the nuclear factor-κB pathway activation, myeloid-derived suppressor cell infiltration, angiogenesis and immune suppression in the tumor microenvironment, all of which are characteristics of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs.

Two-dimensional (2D) materials offer a prospect of membranes that combine negligible gas permeability with high proton conductivity and could outperform the existing proton exchange membranes used in various applications including fuel cells. Graphene oxide (GO), a well-known 2D material, facilitates rapid proton transport along its basal plane but proton conductivity across it remains unknown. It is also often presumed that individual GO monolayers contain a large density of nanoscale pinholes that lead to considerable gas leakage across the GO basal plane. Here we show that relatively large, micrometer-scale areas of monolayer GO are impermeable to gases, including helium, while exhibiting proton conductivity through the basal plane which is nearly two orders of magnitude higher than that of graphene. These findings provide insights into the key properties of GO and demonstrate that chemical functionalization of 2D crystals can be utilized to enhance their proton transparency without compromising gas impermeability. GO monolayers are presumed to invariably contain a large density of nanoscale pinholes. Here the authors present gas and proton transport measurements which show that GO monolayers can be pinhole-free over micrometer-scale areas.

Despite being only one-atom thick, defect-free graphene is considered to be completely impermeable to all gases and liquids 1 – 10 . This conclusion is based on theory 3 – 8 and supported by experiments 1 , 9 , 10 that could not detect gas permeation through micrometre-size membranes within a detection limit of 10 5 to 10 6 atoms per second. Here, using small monocrystalline containers tightly sealed with graphene, we show that defect-free graphene is impermeable with an accuracy of eight to nine orders of magnitude higher than in the previous experiments. We are capable of discerning (but did not observe) permeation of just a few helium atoms per hour, and this detection limit is also valid for all other gases tested (neon, nitrogen, oxygen, argon, krypton and xenon), except for hydrogen. Hydrogen shows noticeable permeation, even though its molecule is larger than helium and should experience a higher energy barrier. This puzzling observation is attributed to a two-stage process that involves dissociation of molecular hydrogen at catalytically active graphene ripples, followed by adsorbed atoms flipping to the other side of the graphene sheet with a relatively low activation energy of about 1.0 electronvolt, a value close to that previously reported for proton transport 11 , 12 . Our work provides a key reference for the impermeability of two-dimensional materials and is important from a fundamental perspective and for their potential applications. Graphene is shown to be impermeable to helium and several other gases, except for hydrogen, which is attributed to the strong catalytic activity of ripples in the graphene sheet.

Fructose consumption and its implications on public health are currently under study. This work reviewed the metabolic fate of dietary fructose based on isotope tracer studies in humans. The mean oxidation rate of dietary fructose was 45.0% ± 10.7 (mean ± SD) in non-exercising subjects within 3–6 hours and 45.8% ± 7.3 in exercising subjects within 2–3 hours. When fructose was ingested together with glucose, the mean oxidation rate of the mixed sugars increased to 66.0% ± 8.2 in exercising subjects. The mean conversion rate from fructose to glucose was 41% ± 10.5 (mean ± SD) in 3–6 hours after ingestion. The conversion amount from fructose to glycogen remains to be further clarified. A small percentage of ingested fructose (<1%) appears to be directly converted to plasma TG. However, hyperlipidemic effects of larger amounts of fructose consumption are observed in studies using infused labeled acetate to quantify longer term de novo lipogenesis. While the mechanisms for the hyperlipidemic effect remain controversial, energy source shifting and lipid sparing may play a role in the effect, in addition to de novo lipogenesis. Finally, approximately a quarter of ingested fructose can be converted into lactate within a few of hours. The reviewed data provides a profile of how dietary fructose is utilized in humans.