What influences the activity of Degrader-Antibody conjugates (DACs).

The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.

Genomic and phenotypic signatures provide insights into the wide adaptation of a global plant invader.

Invasive alien species are primary drivers of biodiversity loss and species extinction. Smooth cordgrass (Spartina alterniflora) is one of the most aggressive invasive plants in coastal ecosystems around the world. However, the genomic bases and evolutionary mechanisms underlying its invasion success have remained largely unknown. Here, we assembled a chromosome-level reference genome and performed phenotypic and population genomic analyses between native US and introduced Chinese populations. Our phenotypic comparisons showed that introduced Chinese populations have evolved competitive traits, such as early flowering time and greater plant biomass, during secondary introductions along China's coast. Population genomic and transcriptomic inferences revealed distinct evolutionary trajectories of low- and high-latitude Chinese populations. In particular, genetic mixture among different source populations, together with independent natural selection acting on distinct target genes, may have resulted in high genome dynamics of the introduced Chinese populations. Our study provides novel phenotypic and genomic evidence showing how smooth cordgrass rapidly adapts to variable environmental conditions in its introduced ranges. Moreover, candidate genes related to flowering time, fast growth, and stress tolerance (i.e., salinity and submergence) provide valuable genetic resources for future improvement of cereal crops.

AisNet: A Universal Interatomic Potential Neural Network with Encoded Local Environment Features.

This paper proposes a new interatomic potential energy neural network, AisNet, which can efficiently predict atomic energies and forces covering different molecular and crystalline materials by encoding universal local environment features, such as elements and atomic positions. Inspired by the framework of SchNet, AisNet consists of an encoding module combining autoencoder with embedding, the triplet loss function and an atomic central symmetry function (ACSF), an interaction module with a periodic boundary condition (PBC), and a prediction module. In molecules, the prediction accuracy of AisNet is comparabel with SchNet on the MD17 dataset, mainly attributed to the effective capture of chemical functional groups through the interaction module. In selected metal and ceramic material datasets, the introduction of ACSF improves the overall accuracy of AisNet by an average of 16.8% for energy and 28.6% for force. Furthermore, a close relationship is found between the feature ratio (i.e., ACSF and embedding) and the force prediction errors, exhibiting similar spoon-shaped curves in the datasets of Cu and HfO2. AisNet produces highly accurate predictions in single-commponent alloys with little data, suggesting the encoding process reduces dependence on the number and richness of datasets. Especially for force prediction, AisNet exceeds SchNet by 19.8% for Al and even 81.2% higher than DeepMD on a ternary FeCrAl alloy. Capable of processing multivariate features, our model is likely to be applied to a wider range of material systems by incorporating more atomic descriptions.

Ageing threatens sustainability of smallholder farming in China.

Rapid demographic ageing substantially affects socioeconomic development1-4 and presents considerable challenges for food security and agricultural sustainability5-8, which have so far not been well understood. Here, by using data from more than 15,000 rural households with crops but no livestock across China, we show that rural population ageing reduced farm size by 4% through transferring cropland ownership and land abandonment (approximately 4 million hectares) in 2019, taking the population age structure in 1990 as a benchmark. These changes led to a reduction of agricultural inputs, including chemical fertilizers, manure and machinery, which decreased agricultural output and labour productivity by 5% and 4%, respectively, further lowering farmers' income by 15%. Meanwhile, fertilizer loss increased by 3%, resulting in higher pollutant emissions to the environment. In new farming models, such as cooperative farming, farms tend to be larger and operated by younger farmers, who have a higher average education level, hence improving agricultural management. By encouraging the transition to new farming models, the negative consequences of ageing can be reversed. Agricultural input, farm size and farmer's income would grow by approximately 14%, 20% and 26%, respectively, and fertilizer loss would reduce by 4% in 2100 compared with that in 2020. This suggests that management of rural ageing will contribute to a comprehensive transformation of smallholder farming to sustainable agriculture in China.

Restoration of native saltmarshes can reverse arthropod assemblages and trophic interactions changed by a plant invasion.

Plant invasions profoundly impact both natural and managed ecosystems, and removal of the invasive plants addresses only part of the problem of restoring impacted areas. The rehabilitation of diverse communities and their ecosystem functions following removal of invasive plants is an important goal of ecological restoration. Arthropod assemblages and trophic interactions are important indicators of the success of restoration, but they have largely been overlooked in saltmarshes. We determined how arthropod assemblages and trophic interactions changed with the invasion of the exotic plant Spartina alterniflora and with the restoration of the native plant Phragmites australis following Spartina removal in a Chinese saltmarsh. We investigated multiple biotic and abiotic variables to gain insight into the factors underlying the changes in arthropod assemblages and trophic structure. We found that although Spartina invasion had changed arthropod diversity, community structure, feeding-guild composition, and the diets of arthropod natural enemies in the saltmarsh, these changes could be reversed by the restoration of native Phragmites vegetation following removal of the invader. The variation in arthropod assemblages and trophic structure were critically associated with four biotic and abiotic variables (aboveground biomass, plant density, leaf N, and soil salinity). Our findings demonstrate the positive effects of controlling invasive plants on biodiversity and nutrient cycling and provide a foundation for assessing the efficacy of ecological restoration projects in saltmarshes.

High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients.

Background. Interferon is a marker of host antiviral immunity, which is disordered in COVID-19 patients. ERV can affect the secretion of interferon through the cGAS-STING pathway. In this study, we explored whether IFN-I and HERV-K (HML-2) were activated in COVID-19 patients and whether there was an interaction between them. Methods. We collected blood samples from COVID-19 patients and healthy controls. We first detected the expression of HERV-K (HML-2) gag, env, and pol genes and IFN-I-related genes between patients and healthy people by qPCR, synchronously detected VERO cells infected with SARS-CoV-2. Then, the chromosome distributions of highly expressed HERV-K (HML-2) gag, env, and pol genes were mapped by the next-generation sequencing results, and GO analysis was performed on the related genes. Results. We found that the HERV-K (HML-2) gag, env, and pol genes were highly expressed in COVID-19 patients and VERO cells infected with SARS-CoV-2. The interferon-related genes IFNB1, ISG15, and IFIT1 were also activated in COVID-19 patients, and GO analysis showed that HERV-K (HML-2) can regulate the secretion of interferon. Conclusions. The high expression of HERV-K (HML-2) might activate the increase of interferon in COVID-19 patients, proving that HERV-K does not only play a negative role in the human body.

Different Profiles of Antibodies and Cytokines Were Found Between Severe and Moderate COVID-19 Patients.

Objectives: Our objective was to determine the antibody and cytokine profiles in different COVID-19 patients. Methods: COVID-19 patients with different clinical classifications were enrolled in this study. The level of IgG antibodies, IgA, IgM, IgE, and IgG subclasses targeting N and S proteins were tested using ELISA. Neutralizing antibody titers were determined by using a toxin neutralization assay (TNA) with live SARS-CoV-2. The concentrations of 8 cytokines, including IL-2, IL-4, IL-6, IL-10, CCL2, CXCL10, IFN-γ, and TNF-α, were measured using the Protein Sample Ella-Simple ELISA system. The differences in antibodies and cytokines between severe and moderate patients were compared by t-tests or Mann-Whitney tests. Results: A total of 79 COVID-19 patients, including 49 moderate patients and 30 severe patients, were enrolled. Compared with those in moderate patients, neutralizing antibody and IgG-S antibody titers in severe patients were significantly higher. The concentration of IgG-N antibody was significantly higher than that of IgG-S antibody in COVID-19 patients. There was a significant difference in the distribution of IgG subclass antibodies between moderate patients and severe patients. The positive ratio of anti-S protein IgG3 is significantly more than anti-N protein IgG3, while the anti-S protein IgG4 positive rate is significantly less than the anti-N protein IgG4 positive rate. IL-2 was lower in COVID-19 patients than in healthy individuals, while IL-4, IL-6, CCL2, IFN-γ, and TNF-α were higher in COVID-19 patients than in healthy individuals. IL-6 was significantly higher in severe patients than in moderate patients. The antibody level of anti-S protein was positively correlated with the titer of neutralizing antibody, but there was no relationship between cytokines and neutralizing antibody. Conclusions: Our findings show the severe COVID-19 patients' antibody levels were stronger than those of moderate patients, and a cytokine storm is associated with COVID-19 severity. There was a difference in immunoglobulin type between anti-S protein antibodies and anti-N protein antibodies in COVID-19 patients. And clarified the value of the profile in critical prevention.

Infection by Diverse HIV-1 Subtypes Leads to Different Elevations in HERV-K Transcriptional Levels in Human T Cell Lines.

Human endogenous retroviruses (HERVs) make up ~8% of the human genome, and for millions of years, they have been subject to strict biological regulation. Many HERVs do not participate in normal physiological activities in the body. However, in some pathological conditions, they can be abnormally activated. For example, HIV infection can cause abnormal activation of HERVs, and under different infection conditions, HERV expression may be different. We observed significant differences in HERV-K transcription levels among HIV-1 subtype-infected individuals. The transcriptional levels in the HERV-K gag region were significantly increased in HIV-1 B subtype-infected patients, while the transcriptional levels in the HERV-K pol region were significantly increased in CRF01_AE and CRF07_BC subtype-infected patients. In vitro, the transcriptional levels of HEVR-K were increased 5-fold and 15-fold in MT2 cells transfected with two different HIV-1 strains (B and CRF01_AE, respectively). However, there was no significant difference in transcriptional levels among regions of HERV-K. When MT2 cells were infected with different subtypes of HIV-1 Tat proteins (B, CRF01_AE), which is constructed by lentiviruses, and the transcription levels of HERV-K were increased 4-fold and 2-fold, respectively. Thus, different subtypes of HIV-1 have different effects on HERV-K transcription levels, which may be caused by many factors, not only Tat protein.

Identification of Two Novel HIV-1 Second-Generation Recombinant Forms (CRF01_AE/CRF07_BC) in Hebei, China.

Homosexual contact is one of the main transmission routes of HIV-1 epidemic in Hebei, China. Several subtypes of HIV are prevalent simultaneously in the population, which always lead to the emergency of unique recombinant forms (URFs). In this study, we reported two new URFs from two HIV-1 positive subjects infected through homosexual contact route in Hebei, China. Phylogenetic and recombinant analyses based on the near full-length genome of the two URFs both revealed the two URFs are the second generation of recombinant strains originated from CRF01_AE and CRF07_BC. The CRF01_AE segments of two URFs located in cluster 4 of CRF01_AE strains in the phylogenetic tree. The emergence of the novel CRF01_AE/CRF07_BC recombinant forms with complicated genomic structures indicated the importance of the continuous monitoring of the HIV-1 epidemic and new URFs among the men who have sex with men populations.

First-principles investigations on the anisotropic elasticity and thermodynamic properties of U3Si2-Al.

U3Si2 has been tested as a new type of nuclear fuel, and Al has been proven to improve its oxidation resistance. However, there is no research on its anisotropic mechanical and thermal properties. The mechanical and thermal properties of Al-alloyed U3Si2 nuclear fuel are calculated on the basis of first principles. Through the phonon dispersion curves, two kinetic stable structures sub-U3Si1.5Al0.5 and sub-U2.5Si2Al0.5(I) are screened out. It is found that the toughness of these two compounds after alloying are significantly improved compared to U3Si2. The three-dimensional Young's modulus shows that, the sub-U3Si1.5Al0.5 formed by Al alloying in U3Si2 maintains a higher mechanical isotropy, while sub-U2.5Si2Al0.5(I) shows higher mechanical anisotropy, which is consistent with the value of A u. The calculation result shows that the lattice thermal conductivity of sub-U3Si1.5Al0.5 and sub-U2.5Si2Al0.5(I) after alloying exhibits high isotropy as the temperature increases.

Phase-field-crystal investigation of the morphology of a steady-state dendrite tip on the atomic scale.

Through phase-field-crystal (PFC) simulations, we investigated, on the atomic scale, the crucial role played by interface energy anisotropy and growth driving force during the morphological evolution of a dendrite tip at low growth driving force. In the layer-by-layer growth manner, the interface energy anisotropy drives the forefront of the dendrite tip to evolve to be highly similar to the corner of the corresponding equilibrium crystal from the aspects of atom configuration and morphology, and thus affects greatly the formation and growth of a steady-state dendrite tip. Meanwhile, the driving force substantially influences the part behind the forefront of the dendrite tip, rather than the forefront itself. However, as the driving force increases enough to change the layer-by-layer growth to the multilayer growth, the morphology of the dendrite tip's forefront is completely altered. Parabolic fitting of the dendrite tip reveals that an increase in the influence of interface energy anisotropy makes dendrite tips deviate increasingly from a parabolic shape. By quantifying the deviations under various interface energy anisotropies and growth driving forces, it is suggested that a perfect parabola is an asymptotic limit for the shape of the dendrite tips. Furthermore, the atomic scale description of the dendrite tip obtained in the PFC simulation is compatible with the mesoscopic results obtained in the phase-field simulation in terms of the dendrite tip's morphology and the stability criterion constant.

Interfacial free energy adjustable phase field crystal model for homogeneous nucleation.

To describe the homogeneous nucleation process, an interfacial free energy adjustable phase-field crystal model (IPFC) was proposed by reconstructing the energy functional of the original phase field crystal (PFC) methodology. Compared with the original PFC model, the additional interface term in the IPFC model effectively can adjust the magnitude of the interfacial free energy, but does not affect the equilibrium phase diagram and the interfacial energy anisotropy. The IPFC model overcame the limitation that the interfacial free energy of the original PFC model is much less than the theoretical results. Using the IPFC model, we investigated some basic issues in homogeneous nucleation. From the viewpoint of simulation, we proceeded with an in situ observation of the process of cluster fluctuation and obtained quite similar snapshots to colloidal crystallization experiments. We also counted the size distribution of crystal-like clusters and the nucleation rate. Our simulations show that the size distribution is independent of the evolution time, and the nucleation rate remains constant after a period of relaxation, which are consistent with experimental observations. The linear relation between logarithmic nucleation rate and reciprocal driving force also conforms to the steady state nucleation theory.

Modified phase-field-crystal model for solid-liquid phase transitions.

A modified phase-field-crystal (PFC) model is proposed to describe solid-liquid phase transitions by reconstructing the correlation function. The effects of fitting parameters of our modified PFC model on the bcc-liquid phase diagram, numerical stability, and solid-liquid interface properties during planar interface growth are examined carefully. The results indicate that the increase of the correlation function peak width at k=k(m) will enhance the stability of the ordered phase, while the increase of peak height at k=0 will narrow the two-phase coexistence region. The third-order term in the free-energy function and the short wave-length of the correlation function have significant influences on the numerical stability of the PFC model. During planar interface growth, the increase of peak width at k=k(m) will decrease the interface width and the velocity coefficient C, but increase the anisotropy of C and the interface free energy. Finally, the feasibility of the modified phase-field-crystal model is demonstrated with a numerical example of three-dimensional dendritic growth of a body-centered-cubic structure.

Precisely detecting atomic position of atomic intensity images.

We proposed a quantitative method to detect atomic position in atomic intensity images from experiments such as high-resolution transmission electron microscopy, atomic force microscopy, and simulation such as phase field crystal modeling. The evaluation of detection accuracy proves the excellent performance of the method. This method provides a chance to precisely determine atomic interactions based on the detected atomic positions from the atomic intensity image, and hence to investigate the related physical, chemical and electrical properties.

TaWRKY68 responses to biotic stresses are revealed by the orthologous genes from major cereals.

WRKY transcription factors have been extensively characterized in the past 20 years, but in wheat, studies on WRKY genes and their function are lagging behind many other species. To explore the function of wheat WRKY genes, we identified a TaWRKY68 gene from a common wheat cultivar. It encodes a protein comprising 313 amino acids which harbors 19 conserved motifs or active sites. Gene expression patterns were determined by analyzing microarray data of TaWRKY68 in wheat and of orthologous genes from maize, rice and barley using Genevestigator. TaWRKY68 orthologs were identified and clustered using DELTA-BLAST and COBALT programs available at NCBI. The results showed that these genes, which are expressed in all tissues tested, had relatively higher levels in the roots and were up-regulated in response to biotic stresses. Bioinformatics results were confirmed by RT-PCR experiments using wheat plants infected by Agrobacterium tumefaciens and Blumeria graminis, or treated with Deoxynivalenol, a Fusarium graminearum-induced mycotoxin in wheat or barley. In summary, TaWRKY68 functions differ during plant developmental stages and might be representing a hub gene function in wheat responses to various biotic stresses. It was also found that including data from major cereal genes in the bioinformatics analysis gave more accurate and comprehensive predictions of wheat gene functions.

Overexpression of a wheat phospholipase D gene, TaPLDα, enhances tolerance to drought and osmotic stress in Arabidopsis thaliana.

Phospholipase D (PLD) is crucial for plant responses to stress and signal transduction, however, the regulatory mechanism of PLD in abiotic stress is not completely understood; especially, in crops. In this study, we isolated a gene, TaPLDα, from common wheat (Triticum aestivum L.). Analysis of the amino acid sequence of TaPLDα revealed a highly conserved C2 domain and two characteristic HKD motifs, which is similar to other known PLD family genes. Further characterization revealed that TaPLDα expressed differentially in various organs, such as roots, stems, leaves and spikelets of wheat. After treatment with abscisic acid (ABA), methyl jasmonate, dehydration, polyethylene glycol and NaCl, the expression of TaPLDα was up-regulated in shoots. Subsequently, we generated TaPLDα-overexpressing transgenic Arabidopsis lines under the control of the dexamethasone-inducible 35S promoter. The overexpression of TaPLDα in Arabidopsis resulted in significantly enhanced tolerance to drought, as shown by reduced chlorosis and leaf water loss, higher relative water content and lower relative electrolyte leakage than the wild type. Moreover, the TaPLDα-overexpressing plants exhibited longer roots in response to mannitol treatment. In addition, the seeds of TaPLDα-overexpressing plants showed hypersensitivity to ABA and osmotic stress. Under dehydration, the expression of several stress-related genes, RD29A, RD29B, KIN1 and RAB18, was up-regulated to a higher level in TaPLDα-overexpressing plants than in wild type. Taken together, our results indicated that TaPLDα can enhance tolerance to drought and osmotic stress in Arabidopsis and represents a potential candidate gene to enhance stress tolerance in crops.

Phase-field-crystal simulation of nonequilibrium crystal growth.

By using the phase field crystal model, we simulate the morphological transition of the crystal growth of equilibrium crystal shape, dendrite, and spherical crystal shape. The relationship among growth morphology, velocity, and density distribution is investigated. The competition between interface energy anisotropy and interface kinetic anisotropy gives rise to the pattern selection of dendritic growth in the diffusion controlled regime under low-crystal-growth velocities. The trapping effect in density diffusion suppresses morphological instabilities under high-crystal-growth velocities, resulting in isotropic growth of spherical crystal. Finally, a morphological phase diagram of crystal growth is constructed as function of the phase field crystal model parameters.