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A major challenge to the characterization of intrinsically disordered regions (IDRs), which are widespread in the proteome, but relatively poorly understood, is the identification of molecular features that mediate functions of these regions, such as short motifs, amino acid repeats and physicochemical properties. Here, we introduce a proteome-scale feature discovery approach for IDRs. Our approach, which we call “reverse homology”, exploits the principle that important functional features are conserved over evolution. We use this as a contrastive learning signal for deep learning: given a set of homologous IDRs, the neural network has to correctly choose a held-out homolog from another set of IDRs sampled randomly from the proteome. We pair reverse homology with a simple architecture and standard interpretation techniques, and show that the network learns conserved features of IDRs that can be interpreted as motifs, repeats, or bulk features like charge or amino acid propensities. We also show that our model can be used to produce visualizations of what residues and regions are most important to IDR function, generating hypotheses for uncharacterized IDRs. Our results suggest that feature discovery using unsupervised neural networks is a promising avenue to gain systematic insight into poorly understood protein sequences.

The inexpensive cost and high manufacture efficient metal wire and arc additive manufacturing (WAAM) system was designed in this work. Its application potential was evaluated from the three aspects of formability, microstructures, and mechanical properties. By using compulsory cooling solution implemented in the open-source WAAM system, the complex-shaped metal parts were deposited completely with no obvious defects, such as cracks, pores, or incomplete fusion. The properties of the WAAM part were evaluated by optical microscopy (OM), scanning electron microscopy (SEM), microhardness, and microtensile test. The results indicate that the formability of metal parts fabricated by the open-source WAAM system was improved by using compulsory cooling solution. The microstructures of the WAAM part are exhibited as granular structure which consisted of the granular ferrite and the residual austenite interspersed with a little pearlite in the intermediate zone. And the average ferrite grain size of non-overlapping layer is relatively smaller than that of overlapping layer. The specimen perpendicular to the building direction exhibits a better mechanical property.

Conversion of tropical peatlands to agriculture leads to a release of carbon from previously stable, long-term storage, resulting in land subsidence that can be a surrogate measure of CO2 emissions to the atmosphere. We present an analysis of recent large-scale subsidence monitoring studies in Acacia and oil palm plantations on peatland in SE Asia, and compare the findings with previous studies. Subsidence in the first 5 yr after drainage was found to be 142 cm, of which 75 cm occurred in the first year. After 5 yr, the subsidence rate in both plantation types, at average water table depths of 0.7 m, remained constant at around 5 cm yr−1. The results confirm that primary consolidation contributed substantially to total subsidence only in the first year after drainage, that secondary consolidation was negligible, and that the amount of compaction was also much reduced within 5 yr. Over 5 yr after drainage, 75 % of cumulative subsidence was caused by peat oxidation, and after 18 yr this was 92 %. The average rate of carbon loss over the first 5 yr was 178 t CO2eq ha−1 yr−1, which reduced to 73 t CO2eq ha−1 yr−1 over subsequent years, potentially resulting in an average loss of 100 t CO2eq ha−1 yr−1 over 25 yr. Part of the observed range in subsidence and carbon loss values is explained by differences in water table depth, but vegetation cover and other factors such as addition of fertilizers also influence peat oxidation. A relationship with groundwater table depth shows that subsidence and carbon loss are still considerable even at the highest water levels theoretically possible in plantations. This implies that improved plantation water management will reduce these impacts by 20 % at most, relative to current conditions, and that high rates of carbon loss and land subsidence are inevitable consequences of conversion of forested tropical peatlands to other land uses.

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro . Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK-3β/β-catenin signaling pathway.

The ability to computationally generate novel yet physically foldable protein structures could lead to new biological discoveries and new treatments targeting yet incurable diseases. Despite recent advances in protein structure prediction, directly generating diverse, novel protein structures from neural networks remains difficult. In this work, we present a diffusion-based generative model that generates protein backbone structures via a procedure inspired by the natural folding process. We describe a protein backbone structure as a sequence of angles capturing the relative orientation of the constituent backbone atoms, and generate structures by denoising from a random, unfolded state towards a stable folded structure. Not only does this mirror how proteins natively twist into energetically favorable conformations, the inherent shift and rotational invariance of this representation crucially alleviates the need for more complex equivariant networks. We train a denoising diffusion probabilistic model with a simple transformer backbone and demonstrate that our resulting model unconditionally generates highly realistic protein structures with complexity and structural patterns akin to those of naturally-occurring proteins. As a useful resource, we release an open-source codebase and trained models for protein structure diffusion. The ability to engineer novel protein structures has tremendous scientific and therapeutic impact. Here, authors develop a generative model acting upon an angular representation of protein structures to create high quality protein backbones.

A bstract Consider a system consisting of D p and D p ′, placed parallel at a separation and with p − p ′ = 2 n (assuming p ≥ p ′, the integer n ≥ 0 and p ′ > 0). When either D p or D p ′ carries a worldvolume electric flux, one in general expects a non-vanishing open string pair production due to the pair of virtual open string/anti open string connecting the two D branes under the action of the applied flux. However, this will not be true for p ′ = 0 and p = 2 , 4 , 6 when the D p carries a pure electric flux. In this note, we will explore the case for which a finite non-vanishing open string pair production rate can indeed be produced when a certain worldvolume flux is applied to the Dp brane and understand the physics behind.

The correct establishment and maintenance of cell polarity are crucial for normal cell physiology and tissue homeostasis. Conversely, loss of cell polarity, tissue disorganisation and excessive cell growth are hallmarks of cancer. In this review, we focus on identifying the stages of tumoural development that are affected by the loss or deregulation of epithelial cell polarity. Asymmetric division has recently emerged as a major regulatory mechanism that controls stem cell numbers and differentiation. Links between cell polarity and asymmetric cell division in the context of cancer will be examined. Apical–basal polarity and cell–cell adhesion are tightly interconnected. Hence, how loss of cell polarity in epithelial cells may promote epithelial mesenchymal transition and metastasis will also be discussed. Altogether, we present the argument that loss of epithelial cell polarity may have an important role in both the initiation of tumourigenesis and in later stages of tumour development, favouring the progression of tumours from benign to malignancy.

Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

Foundation models such as scGPT and Geneformer have not been rigorously evaluated in a setting where they are used without any further training (i.e., zero-shot). Understanding the performance of models in zero-shot settings is critical to applications that exclude the ability to fine-tune, such as discovery settings where labels are unknown. Our evaluation of the zero-shot performance of Geneformer and scGPT suggests that, in some cases, these models may face reliability challenges and could be outperformed by simpler methods. Our findings underscore the importance of zero-shot evaluations in development and deployment of foundation models in single-cell research.

Soil erosion and terrestrial deposition of soil organic carbon (SOC) can potentially play a significant role in global carbon cycling. Assessing the redistribution of SOC during erosion and subsequent transport and burial is of critical importance. Using hydrological records of soil erosion and sediment load, and compiled organic carbon (OC) data, estimates of the eroded soils and OC induced by water in the Yellow River basin during the period 1950–2010 were assembled. The Yellow River basin has experienced intense soil erosion due to combined impact of natural process and human activity. Over the period, 134.2 ± 24.7 Gt of soils and 1.07 ± 0.15 Gt of OC have been eroded from hillslopes based on a soil erosion rate of 1.7–2.5 Gt yr−1. Approximately 63% of the eroded soils were deposited in the river system, while only 37% were discharged into the ocean. For the OC budget, approximately 0.53 ± 0.21 Gt (49.5%) was buried in the river system, 0.25 ± 0.14 Gt (23.5%) was delivered into the ocean, and the remaining 0.289 ± 0.294 Gt (27%) was decomposed during the erosion and transport processes. This validates the commonly held assumption that 20–40% of the eroded OC would be oxidized after erosion. Erosion-induced OC redistribution on the landscape likely represented a carbon source, although a large proportion of OC was buried. In addition, about half of the terrestrially redeposited OC (49.4%) was buried behind dams, revealing the importance of dam trapping in sequestering the eroded OC. Although several uncertainties need to be better constrained, the obtained budgetary results provide a means of assessing the redistribution of the eroded OC within the Yellow River basin. Human activities have significantly altered its redistribution pattern over the past decades.