Developing deep LSTMs with later temporal attention for predicting COVID-19 severity, clinical outcome, and antibody level by screening serological indicators over time.

OBJECTIVE: The clinical course of COVID-19, as well as the immunological reaction, is notable for its extreme variability. Identifying the main associated factors might help understand the disease progression and physiological status of COVID-19 patients. The dynamic changes of the antibody against Spike protein are crucial for understanding the immune response. This work explores a temporal attention (TA) mechanism of deep learning to predict COVID-19 disease severity, clinical outcomes, and Spike antibody levels by screening serological indicators over time. METHODS: We use feature selection techniques to filter feature subsets that are highly correlated with the target. The specific deep Long Short-Term Memory (LSTM) models are employed to capture the dynamic changes of disease severity, clinical outcome, and Spike antibody level. We also propose deep LSTMs with a TA mechanism to emphasize the later blood test records because later records often attract more attention from doctors. RESULTS: Risk factors highly correlated with COVID-19 are revealed. LSTM achieves the highest classification accuracy for disease severity prediction. Temporal Attention Long Short-Term Memory (TA-LSTM) achieves the best performance for clinical outcome prediction. For Spike antibody level prediction, LSTM achieves the best permanence. CONCLUSION: The experimental results demonstrate the effectiveness of the proposed models. The proposed models can provide a computer-aided medical diagnostics system by simply using time series of serological indicators.

Changing soil available substrate primarily caused by fertilization management contributed more to soil respiration temperature sensitivity than microbial community thermal adaptation.

Substrate depletion and microbial community thermal adaptation are major mechanisms that regulate the temperature sensitivity (Q10) of soil microbial respiration. Traditionally, the Q10 of soil microbial respiration is measured using laboratory incubation, which has limits in the continuous input of available substrates and the time scale for microbial community thermal adaptation. How the available substrate and the soil microbial community regulate the Q10 of soil microbial respiration under natural warming conditions remains unclear. To fill this gap in knowledge, a long-term field experiment was conducted consisting of two years of soil respiration observations combined with a soil available substrate and microbial community thermal adaptation analysis under seasonal warming conditions. The Q10 of soil respiration was calculated using the square root method, and it was more affected by the available substrate than by microbial community thermal adaptation. Fertilization management has a stronger effect on soil available substrate than temperature. As the temperature increased, NH4-N proved itself to be important for the bacterial community in the process of Q10 regulation, while dissolved organic carbon and nitrogen were key factors for the fungal community. Based on the niche breadth of microbial community composition, the changing Q10 of the soil respiration was not only closely associated with the specialist community, but also the generalist and neutralist communities. Furthermore, bacterial community thermal adaptation primarily occurred through shifts in the abundances of specialists and neutralists, while changes in species richness and species replacement occurred for the fungal generalists and neutralists. This work indicates that changing available nitrogen and DOC primarily caused by fertilization management contributed more in regulating the Q10 of soil microbial respiration than microbial community thermal adaptation, and there are different mechanisms for bacterial and fungal community thermal adaptation under warming.

Site-specific controlled-release nanoparticles for immune reprogramming via dual metabolic inhibition against triple-negative breast cancer.

Metabolic heterogeneity and the tumor immunosuppressive microenvironment (TIME) of triple-negative breast cancer (TNBC) hinder therapeutic effectiveness. Although emerging metabolic therapy and immunotherapy show promise, they are limited by off-target effects and immune escape. Here, a redox-activatable, sequentially-releasing nanoparticle (AMANC@M) for tumor-targeted delivery of anticancer agents and CRISPR/Cas9 has been developed. AMANC@M can reverse the TIME through dual metabolic inhibition, thereby enhancing TNBC therapy. AMANC@M demonstrates excellent biosafety and targets tumors precisely through biomimetic hybrid membrane-mediated homologous homing and the enhanced permeability and retention (EPR) effect. Once internalized into tumor cells, the CRISPR/Cas9 system ("energy nanolock") is released through glutathione (GSH) cleavage and effectively knocks down the expression of lactate dehydrogenase A (LDHA) to suppress glycolysis. After peeling off of the gene editing shell, a newly synthesized targeted drug, CPI-Z2 ("nutrihijacker" and "energy nanolock"), is released in a controlled manner to block the mitochondrial tricarboxylic acid (TCA) cycle. Nitric oxide (NO) produced from loaded L-arginine enhances the efficiency of CPI-Z2 and reduces drug resistance. Combined with NO therapy, both blockades of nutrients and energy production transform the hypoxia and acidic TIME into an immunocompetent tumor microenvironment (TME) for tumor elimination. Furthermore, AMANC@M offers capabilities for photothermal (PT) therapy and provides clear imaging through PT, photoacoustic (PA), or computed tomography (CT) signals in tumor tissue. Thus, this study provides a new and promising sequentially stimuli-responsive targeting strategy for nanoparticle development, making it a potential treatment candidate for TNBC and other tumors.

Tissue expression of the SARS-CoV-2 cell receptor gene ACE2 in children.

Coronavirus disease 2019 (COVID-19) has become a significant global public health problem. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the disease, utilizes angiotensin-converting enzyme II (ACE2) as a major functional receptor to enter host cells. No study has systematically assessed ACE2 expression in multiple tissues in children. This study investigated ACE2 expression and ACE2 protein's histological distribution in various organs in paediatric patients (the small intestine, thymus, heart and lungs). Our study revealed that ACE2 was highly expressed in enterocytes of the small intestine and widely expressed in the myocardium of heart tissues. The most notable finding was the positive staining of ACE2 in the Hassall's corpuscles epithelial cells. Negligible ACE2 expression in the lung tissues may contribute to a lower risk of infection and fewer symptoms of pneumonia in children than in adults with COVID-19 infection. These findings provide initial evidence for understanding SARS-CoV-2 pathogenesis and prevention strategies in paediatric clinical practice, which should be applicable for all children worldwide.

Natural variation of GmFATA1B regulates seed oil content and composition in soybean.

Soybean (Glycine max) produces seeds that are rich in unsaturated fatty acids and is an important oilseed crop worldwide. Seed oil content and composition largely determine the economic value of soybean. Due to natural genetic variation, seed oil content varies substantially across soybean cultivars. Although much progress has been made in elucidating the genetic trajectory underlying fatty acid metabolism and oil biosynthesis in plants, the causal genes for many quantitative trait loci (QTLs) regulating seed oil content in soybean remain to be revealed. In this study, we identified GmFATA1B as the gene underlying a QTL that regulates seed oil content and composition, as well as seed size in soybean. Nine extra amino acids in the conserved region of GmFATA1B impair its function as a fatty acyl-acyl carrier protein thioesterase, thereby affecting seed oil content and composition. Heterogeneously overexpressing the functional GmFATA1B allele in Arabidopsis thaliana increased both the total oil content and the oleic acid and linoleic acid contents of seeds. Our findings uncover a previously unknown locus underlying variation in seed oil content in soybean and lay the foundation for improving seed oil content and composition in soybean.

Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy.

In many types of cancers, pyruvate dehydrogenase kinase (PDK) is abnormally overexpressed and has become a promising target for cancer therapy. However, few highly effective inhibitors of PDK have been reported to date. Herein, we designed and synthesized a series of PDK inhibitors based on dichloroacetate (DCA) and arsenicals. Of the 27 compounds, 1f demonstrated PDK inhibition with high efficiency at a cellular level (IC50 = 2.0 µM) and an enzyme level (EC50 = 68 nM), far more effective than that of DCA. In silico, in vitro, and in vivo studies demonstrated that 1f inhibited PDK, shifted the energy metabolism from aerobic glycolysis to oxidative phosphorylation, and induced cell apoptosis. Moreover, new 1f-loaded nanoparticles were developed, and the administration of high-drug-loading nanoparticles (0.15 mg/kg) caused up to 90% tumor shrinkage without any apparent toxicity. Hence, this study provided a novel metabolic therapy for cancer treatment.

Synthesis of chiral malonates by α-alkylation of 2,2-diphenylethyl tert-butyl malonates via enantioselective phase-transfer catalysis.

An efficient synthetic approach for chiral malonates was established via enantioselective phase transfer catalysis. The α-alkylation of 2,2-diphenylethyl tert-butyl α-methylmalonates with (S,S)-3,4,5-trifluorophenyl-NAS bromide as a phase-transfer catalyst under phase-transfer catalytic conditions successfully produced corresponding α-methyl-α-alkylmalonates; these compounds are versatile chiral building blocks containing a quaternary carbon center in high chemical yields (up to 99%) with excellent enantioselectivities (up to 98% ee). α,α-Dialkylmalonates were selectively hydrolyzed to the corresponding chiral malonic monoacids under basic (KOH/MeOH) and acidic conditions (TFA/CH2Cl2), showing the practicality of the method.

Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy.

Boron neutron capture therapy (BNCT) was clinically approved in 2020 and exhibits remarkable tumour rejection in preclinical and clinical studies. It is binary radiotherapy that may selectively deposit two deadly high-energy particles (4He and 7Li) within a cancer cell. As a radiotherapy induced by localized nuclear reaction, few studies have reported its abscopal anti-tumour effect, which has limited its further clinical applications. Here, we engineer a neutron-activated boron capsule that synergizes BNCT and controlled immune adjuvants release to provoke a potent anti-tumour immune response. This study demonstrates that boron neutron capture nuclear reaction forms considerable defects in boron capsule that augments the drug release. The following single-cell sequencing unveils the fact and mechanism that BNCT heats anti-tumour immunity. In female mice tumour models, BNCT and the controlled drug release triggered by localized nuclear reaction causes nearly complete regression of both primary and distant tumour grafts.

Long-term chemical fertilization results in a loss of temporal dynamics of diazotrophic communities in the wheat rhizosphere.

Diazotrophs are potential bacterial biofertilizers with efficacy for plant nutrition, which convert atmospheric N2 into plant available nitrogen. Although they are known to respond strongly to fertilization, little is known about the temporal dynamics of diazotrophic communities throughout plant developmental under different fertilization regimes. In this study, we investigated diazotrophic communities in the wheat rhizosphere at four developmental stages under three long-term fertilization regimes: no fertilizer (Control), chemical NPK fertilizer only (NPK), and NPK fertilizer plus cow manure (NPKM). Fertilization regime had greater effect (explained of 54.9 %) on diazotrophic community structure than developmental stage (explained of 4.8 %). NPK fertilization decreased the diazotrophic diversity and abundance to one-third of the Control, although this was largely recovered by the addition of manure. Meanwhile, Control treatment resulted in significant variation in diazotrophic abundance, diversity, and community structure (P = 0.001) depending on the developmental stage, while the NPK fertilization resulted in the loss of temporal dynamics of the diazotrophic community (P = 0.330), which could be largely recovered by the addition of manure (P = 0.011). Keystone species identified in this study were quite different among the four developmental stages under Control and NPKM treatment but were similar among stages under NPK treatment. These findings suggest that long-term chemical fertilization not only reduces diazotrophic diversity and abundance, but also results in a loss of temporal dynamics of rhizosphere diazotrophic communities.

Overexpression of GmWRKY172 enhances cadmium tolerance in plants and reduces cadmium accumulation in soybean seeds.

Introduction: Cadmium (Cd) stress is a significant threat to soybean production, and enhancing Cd tolerance in soybean is the focus of this study. The WRKY transcription factor family is associated with abiotic stress response processes. In this study, we aimed to identify a Cd-responsive WRKY transcription factor GmWRKY172 from soybean and investigate its potential for enhancing Cd tolerance in soybean. Methods: The characterization of GmWRKY172 involved analyzing its expression pattern, subcellular localization, and transcriptional activity. To assess the impact of GmWRKY172, transgenic Arabidopsis and soybean plants were generated and examined for their tolerance to Cd and Cd content in shoots. Additionally, transgenic soybean plants were evaluated for Cd translocation and various physiological stress indicators. RNA sequencing was performed to identify the potential biological pathways regulated by GmWRKY172. Results: GmWRKY172 was significantly upregulated by Cd stress, highly expressed in leaves and flowers, and localized to the nucleus with transcriptional activity. Transgenic plants overexpressing GmWRKY172 showed enhanced Cd tolerance and reduced Cd content in shoots compared to WT. Lower Cd translocation from roots to shoots and seeds was also observed in transgenic soybean. Under Cd stress, transgenic soybean accumulated less malondialdehyde (MDA) and hydrogen peroxide (H2O2) than WT plants, with higher flavonoid and lignin contents, and peroxidase (POD) activity. RNA sequencing analysis revealed that many stress-related pathways were regulated by GmWRKY172 in transgenic soybean, including flavonoid biosynthesis, cell wall synthesis, and peroxidase activity. Discussion: Our findings demonstrated that GmWRKY172 enhances Cd tolerance and reduces seed Cd accumulation in soybean by regulating multiple stress-related pathways, and could be a promising candidate for breeding Cd-tolerant and low Cd soybean varieties.

A water quality assessment method based on an improved grey relational analysis and particle swarm optimization multi-classification support vector machine.

Most of the water quality indicators that affect the results of river water quality assessment are gray and localized, thus the correlation between water quality indicators can be calculated using gray correlation analysis (GRA).However, GRA takes equal weighting for water quality indicators and does not take into account the weighting of the indicators. Therefore, this paper proposes a river water quality assessment method based on improved grey correlation analysis (ACGRA) andparticle swarm optimization multi-classification support vector machine (PSO-MSVM) for assessing river water environment quality. Firstly, the combination weights of water quality indicators were calculated using Analytic Hierarchy Process (AHP)AHP and Criteria Importance Though Intercrieria Correlation (CRITIC)CRITIC, and then the correlation between water quality indicators was calculated for feature selection. Secondly, the PSO-MSVM model was established using the water quality indicators obtained by ACGRA as input parameters for water environment quality assessment. The river water environment assessment methods of ACGRA and PSO-MSVM were applied to the evaluation of water environment quality in different watersheds in the country. Accuracy, precision, recall and root mean square errorRMSE were also introduced as model evaluation criteria. The results show that the river water environment assessment methods based on ACGRA and PSO-MSVM can evaluate the water environment quality more accurately.

Vorticity wave interaction, Krein collision, and exceptional points in shear flow instabilities.

We relate the model of vorticity wave interaction to Krein collision, PT-symmetry breaking, and the formation of exceptional points in shear flow instabilities. We show that the dynamical system of coupled vorticity waves is a pseudo-Hermitian system with nonreciprocal coupling terms. Krein signatures of the eigenvalues are illustrated as the signs of the action of the vorticity waves. Interaction between positive-action and negative-action vorticity waves then corresponds to the Krein collision between eigenvalues with opposite Krein signatures, the spontaneous breaking of PT symmetry, and the formation of exceptional points. The control parameter of the PT-symmetry-breaking bifurcation is the ratio between frequency detuning and coupling strength of the vorticity waves. The critical behavior near the exceptional points is described as a transition between phase-locking and phase-slip dynamics of the vorticity waves. The phase-slip dynamics correspond to nonmodal, transient growth of perturbations in the regime of unbroken PT symmetry, and the phase-slip frequency Ω∝|k-k_{c}|^{1/2} shares the same critical exponent with the phase rigidity of system eigenvectors.

Prognostic significance of SPARC expression in non-small cell lung cancer: A meta-analysis and bioinformatics analysis.

The aim of the present study was to elucidate the significance of secreted protein acidic and cysteine rich (SPARC) expression in non-small cell lung cancer (NSCLC) in terms of clinicopathology, immune-cell infiltration and survival prognosis. A meta-analysis and bioinformatics analysis were performed using studies retrieved with PubMed, Web of Science, Wanfang Data and the Chinese National Knowledge Infrastructure databases. The meta-analysis suggested that, compared with normal tissues, SPARC expression was elevated in NSCLC tissues. The expression of SPARC was not significantly associated with TNM stage and lymph-node metastasis, and was positively associated with patient gender. Regarding the differential expression of SPARC and the relationship between expression levels and survival, the Oncomine database was consulted and Kaplan-Meier curves were drawn. It was indicated that SPARC mRNA expression levels were higher in NSCLC tissues than in normal tissues. Low expression of SPARC mRNA was negatively associated with overall survival, first progression survival and post-progression survival of patients. Further exploration of the relationship between SPARC expression and survival by univariate analysis indicated that TNM stage, lymph node metastasis, distant metastasis and depth of infiltration of lung cancer were negatively associated with patient prognosis. Cox multifactorial analysis suggested that SPARC expression levels and TNM stage were risk factors significantly affecting the prognosis of patients with NSCLC. Analysis with the GEPIA and UALCAN databases further indicated that the mRNA expression level of SPARC in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) was higher than that in normal lung tissue, and the SPARC expression levels were affected by factors such as the TNM stage of lung cancer. A lower the level of SPARC mRNA expression was associated with a better relative survival prognosis of patients. In the Human Protein Atlas database, the expression level of SPARC protein was higher in LUAD and LUSC than in normal lung tissue. In the Timer database, the expression level of SPARC was closely linked to immune cells related to the occurrence of lung cancer, and the degree of immune-cell infiltration and SPARC protein expression were closely related to the prognosis of patients with lung cancer. Immune cells were indicated to exhibit significant inhibition of DNA proliferation mutation mechanisms in lung cancer (P<0.05). In summary, SPARC expression may be used as a valuable indicator of prognosis in patients with NSCLC, which may provide new approaches for preventative treatment.

Radiotherapy-Induced Cleavage of Quaternary Ammonium Groups Activates Prodrugs in Tumors.

Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor-selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy-triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e-aq ) from water radiolysis. The subsequently released tertiary amines can be anti-cancer toxins or readily release functional molecules via 1,6-elimination. This radiotherapy-induced cleavage works successfully in living cells and tumor-bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first-line treatment for over 50 % of cancer patients.

Radiotherapy Reduces N-Oxides for Prodrug Activation in Tumors.

Precisely activating chemotherapeutic prodrugs in a tumor-selective manner is an ideal way to cure cancers without causing systemic toxicities. Although many efforts have been made, developing spatiotemporally controllable activation methods is still an unmet challenge. Here, we report a novel prodrug activation strategy using radiotherapy (X-ray). Due to its precision and deep tissue penetration, X-ray matches the need for altering molecules in tumors through water radiolysis. We first demonstrated that N-oxides can be effectively reduced by hydrated electrons (e-aq) generated from radiation both in tubes and living cells. A screening is performed to investigate the structure-reduction relationship and mechanism of the e-aq-mediated reductions. We then apply the strategy to activate N-oxide prodrugs. The anticancer drug camptothecin (CPT)-based N-oxide prodrug shows a remarkable anticancer effect upon activation by radiotherapy. This radiation-induced in vivo chemistry may enable versatile designs of radiotherapy-activated prodrugs, which are of remarkable clinical relevance, as over 50% of cancer patients take radiotherapy.

Boron encapsulated in a liposome can be used for combinational neutron capture therapy.

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies.

Group membership moderates the process of making trust judgments based on facial cues.

Trust is a foundation of interpersonal communication. Faces have a significant impact on trust judgments, and separate research demonstrates that group membership also influences trust judgments. However, it remains unclear whether and how group membership moderates the effect of face trustworthiness on trust judgments and investment decisions. In the present research, two experiments were conducted to explore the moderating effect of group membership (i.e., in-group vs. out-group) on perceptions of facial trustworthiness and trust judgments. Results showed that participants invested significantly more money on trials with trustworthy faces than trials with untrustworthy faces. Additionally, there was a significant interaction between group membership and facial trustworthiness; the investment difference between trustworthy faces and untrustworthy faces was greater for trials with in-group member faces than out-group member faces. These findings indicate that top-down and bottom-up cues jointly influence behavioral decisions.

Identification of major QTLs for soybean seed size and seed weight traits using a RIL population in different environments.

Introduction: The seed weight of soybean [Glycine max (L.) Merr.] is one of the major traits that determine soybean yield and is closely related to seed size. However, the genetic basis of the synergistic regulation of traits related to soybean yield is unclear. Methods: To understand the molecular genetic basis for the formation of soybean yield traits, the present study focused on QTLs mapping for seed size and weight traits in different environments and target genes mining. Results: A total of 85 QTLs associated with seed size and weight traits were identified using a recombinant inbred line (RIL) population developed from Guizao1×B13 (GB13). We also detected 18 environmentally stable QTLs. Of these, qSL-3-1 was a novel QTL with a stable main effect associated with seed length. It was detected in all environments, three of which explained more than 10% of phenotypic variance (PV), with a maximum of 15.91%. In addition, qSW-20-3 was a novel QTL with a stable main effect associated with seed width, which was identified in four environments. And the amount of phenotypic variance explained (PVE) varied from 9.22 to 21.93%. Five QTL clusters associated with both seed size and seed weight were summarized by QTL cluster identification. Fifteen candidate genes that may be involved in regulating soybean seed size and weight were also screened based on gene function annotation and GO enrichment analysis. Discussion: The results provide a biologically basic reference for understanding the formation of soybean seed size and weight traits.

The effects of combined cognitive training on prospective memory in older adults with mild cognitive impairment.

This study aimed to assess the effects of combined cognitive training on prospective memory ability of older adults with mild cognitive impairment (MCI). A total of 113 participants were divided into a control group and three intervention groups. Over three months, the control group received only community education without any training, whereas for the first six weeks, an executive function training group received executive function training, a memory strategy training group received semantic encoding strategy training, and the combined cognitive training group received executive function training twice a week for the first six weeks, and semantic encoding strategy training twice a week for the next six weeks. The combined cognitive training group showed improvement on the objective neuropsychological testing (Montreal Cognitive Assessment scale). The memory strategy training group showed improvement on the self-evaluation scales (PRMQ-PM). Combined cognitive training improved the prospective memory and cognitive function of older adults with MCI.