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Abstract Bacteria colonize almost all parts of the human body and can differ significantly. However, the population level transcriptomics measurements can only describe the average bacteria population behaviors, ignoring the heterogeneity among bacteria. Here, we report a droplet-based high-throughput single-microbe RNA-seq assay (smRandom-seq), using random primers for in situ cDNA generation, droplets for single-microbe barcoding, and CRISPR-based rRNA depletion for mRNA enrichment. smRandom-seq showed a high species specificity (99%), a minor doublet rate (1.6%), a reduced rRNA percentage (32%), and a sensitive gene detection (a median of ~1000 genes per single E. coli). Furthermore, smRandom-seq successfully captured transcriptome changes of thousands of individual E. coli and discovered a few antibiotic resistant subpopulations displaying distinct gene expression patterns of SOS response and metabolic pathways in E. coli population upon antibiotic stress. smRandom-seq provides a high-throughput single-microbe transcriptome profiling tool that will facilitate future discoveries in microbial resistance, persistence, microbe-host interaction, and microbiome research.

Abstract Tumor heterogeneity and its drivers impair tumor progression and cancer therapy. Single‐cell RNA sequencing is used to investigate the heterogeneity of tumor ecosystems. However, most methods of scRNA‐seq amplify the termini of polyadenylated transcripts, making it challenging to perform total RNA analysis and somatic mutation analysis.Therefore, a high‐throughput and high‐sensitivity method called snHH‐seq is developed, which combines random primers and a preindex strategy in the droplet microfluidic platform. This innovative method allows for the detection of total RNA in single nuclei from clinically frozen samples. A robust pipeline to facilitate the analysis of full‐length RNA‐seq data is also established. snHH‐seq is applied to more than 730 000 single nuclei from 32 patients with various tumor types. The pan‐cancer study enables it to comprehensively profile data on the tumor transcriptome, including expression levels, mutations, splicing patterns, clone dynamics, etc. New malignant cell subclusters and exploring their specific function across cancers are identified. Furthermore, the malignant status of epithelial cells is investigated among different cancer types with respect to mutation and splicing patterns. The ability to detect full‐length RNA at the single‐nucleus level provides a powerful tool for studying complex biological systems and has broad implications for understanding tumor pathology.

Abstract Precise control of exciton confinement in metal halide perovskites is critical to the development of high‐performance, stable optoelectronic devices. A significant hurdle is the swift completion of ionic metathesis reactions, often within seconds, making consistent control challenging. Herein, the introduction of different steric hindrances in a Cs+ sublattice within CsYb2F7 is reported, which effectively modulates the reaction rate of Cs+ with lead (Pb2+) and halide ions in solution, extending the synthesis time for perovskite nanostructures to tens of minutes. Importantly, the Cs+ sublattice provides a crystal facet‐dependent preference for perovskite growth and thus exciton confinement, allowing the simultaneous occurrence of up to six emission bands of CsPbBr3. Moreover, the rigid CsYb2F7 nano template offers high activation energy and enhances the stability of the resulting perovskite nanostructures. This methodology provides a versatile approach to synthesizing functional heterostructures. Its robustness is demonstrated by in‐situ growth of perovskite nanostructures on Cs+‐mediated metal‐organic frameworks.

Abstract Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank for clinical history and follow-up data. It is still challenging to achieve single cell/nucleus RNA (sc/snRNA) profile in FFPE tissues. Here, we develop a droplet-based snRNA sequencing technology (snRandom-seq) for FFPE tissues by capturing full-length total RNAs with random primers. snRandom-seq shows a minor doublet rate (0.3%), a much higher RNA coverage, and detects more non-coding RNAs and nascent RNAs, compared with state-of-art high-throughput scRNA-seq technologies. snRandom-seq detects a median of >3000 genes per nucleus and identifies 25 typical cell types. Moreover, we apply snRandom-seq on a clinical FFPE human liver cancer specimen and reveal an interesting subpopulation of nuclei with high proliferative activity. Our method provides a powerful snRNA-seq platform for clinical FFPE specimens and promises enormous applications in biomedical research.

Abstract Background Extravillous trophoblast (EVT) cell invasion is a tightly regulated process that requires for a normal pregnancy. The epithelial-mesenchymal transition (EMT) has been implicated in EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-beta (TGF-β) superfamily, is expressed in the human placenta and promotes EVT cell invasion by upregulating the expression of matrix metalloproteinase 2 (MMP2). However, the underlying molecular mechanism of GDF-8-induced MMP2 expression remains undetermined. Therefore, the present study aims to examine the role of Snail and Slug, the EMT-related transcriptional regulators, in GDF-8-stimulated MMP2 expression and cell invasion in HTR-8/SVneo human EVT cell line and primary cultures of human EVT cells. Methods HTR-8/SVneo and primary cultures of human EVT cells were used to examine the effect of GDF-8 on MMP2 expression and explore the underlying mechanism. For gene silencing and overexpression, the HTR-8/SVneo cell line was used to make the experiments more technically feasible. The cell invasiveness was measured by Matrigel-coated transwell invasion assay. Results GDF-8 stimulated MMP2 expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effect of GDF-8 on MMP2 expression was blocked by the inhibitor of TGF-β type-I receptors, SB431542. Treatment with GDF-8 upregulated Snail and Slug expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effects of GDF-8 on Snail and Slug expression were blocked by pretreatment of SB431542 and siRNA-mediated knockdown of SMAD4. Interestingly, using the siRNA knockdown approach, our results showed that Snail but not Slug was required for the GDF-8-induced MMP2 expression and cell invasion in HTR-8/SVneo cells. The reduction of MMP2 expression in the placentas with preeclampsia (PE) was also observed. Conclusions These findings discover the physiological function of GDF-8 in the human placenta and provide important insights into the regulation of MMP2 expression in human EVT cells. Video Abstract

Abstract Background Aging degrades the balance and locomotion ability due to frailty and pathological conditions. This demands balance rehabilitation and assistive technologies that help the affected population to regain mobility, independence, and improve their quality of life. While many overground gait rehabilitation and assistive robots exist in the market, none are designed to be used at home or in community settings. Methods A device named Mobile Robotic Balance Assistant (MRBA) is developed to address this problem. MRBA is a hybrid of a gait assistive robot and a powered wheelchair. When the user is walking around performing activities of daily living, the robot follows the person and provides support at the pelvic area in case of loss of balance. It can also be transformed into a wheelchair if the user wants to sit down or commute. To achieve instability detection, sensory data from the robot are compared with a predefined threshold; a fall is identified if the value exceeds the threshold. The experiments involve both healthy young subjects and an individual with spinal cord injury (SCI). Spatial Parametric Mapping is used to assess the effect of the robot on lower limb joint kinematics during walking. The instability detection algorithm is evaluated by calculating the sensitivity and specificity in identifying normal walking and simulated falls. Results When walking with MRBA, the healthy subjects have a lower speed, smaller step length and longer step time. The SCI subject experiences similar changes as well as a decrease in step width that indicates better stability. Both groups of subjects have reduced joint range of motion. By comparing the force sensor measurement with a calibrated threshold, the instability detection algorithm can identify more than 93% of self-induced falls with a false alarm rate of 0%. Conclusions While there is still room for improvement in the robot compliance and the instability identification, the study demonstrates the first step in bringing gait assistive technologies into homes. We hope that the robot can encourage the balance-impaired population to engage in more activities of daily living to improve their quality of life. Future research includes recruiting more subjects with balance difficulty to further refine the device functionalities.

Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed “degradability”, is largely unknown. Here, we developed a machine learning model, model-free analysis of protein degradability (MAPD), to predict degradability from features intrinsic to protein targets. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds [with an area under the precision–recall curve (AUPRC) of 0.759 and an area under the receiver operating characteristic curve (AUROC) of 0.775] and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins (including proteins encoded by 278 cancer genes) that may be tractable to TPD drug development.

Background Non-suicidal self-injury (NSSI) is a frequent and prominent phenomenon in major depressive disorder (MDD). Even though its prevalence and risk factors are relatively well understood, the potential mechanisms of NSSI in MDD remain elusive.Aims To review present evidence related to the potential mechanisms of NSSI in MDD.Methods According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, articles for this systematic review were searched on Medline (through PubMed), Embase (through Elsevier), PsycINFO (through OVID) and Web of Science databases for English articles, as well as China National Knowledge Infrastructure (CNKI), SinoMed, Wanfang Data, and the Chongqing VIP Chinese Science and Technology Periodical (VIP) Databases for Chinese articles published from the date of inception to 2 August 2022. Two researchers (BW, HZ) independently screened studies based on inclusion and exclusion criteria and assessed their quality.Results A total of 25 157 studies were searched. Only 25 of them were ultimately included, containing 3336 subjects (1535 patients with MDD and NSSI, 1403 patients with MDD without NSSI and 398 HCs). Included studies were divided into 6 categories: psychosocial factors (11 studies), neuroimaging (8 studies), stress and hypothalamic-pituitary-adrenal (HPA) axis (2 studies), pain perception (1 study), electroencephalogram (EEG) (2 studies) and epigenetics (1 study).Conclusions This systematic review indicates that patients with MDD and NSSI might have specific psychosocial factors, aberrant brain functions and neurochemical metabolisms, HPA axis dysfunctions, abnormal pain perceptions and epigenetic alterations.

Abstract Background Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC. Methods To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme −/− mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells. Results In the CAC model, Gsdme −/− mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway. Conclusion GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.

This paper develops a novel nonlinear adaptive robust filter called the multiple-step randomly delayed variational Bayesian adaptive high-degree cubature Huber-based filter (MRD-VBAHCHF) for a class of nonlinear stochastic systems whose measurements are randomly delayed by multiple sampling times and corrupted by contaminated Gaussian noise with unknown covariance. First, a system with randomly delayed measurement is modeled in terms of multiple Bernoulli random variables. Then, the multiple-step randomly delayed high-degree cubature Kalman filter (MRD-HCKF) is derived by employing the fifth-degree cubature rule to compute the mean and covariance of the nonlinear equations in the system model. Next, the MRD-HCKF is modified to the MRD-VBAHCHF by incorporating the variational Bayesian theory and Huber technique for estimating the measurement noise covariance online and suppressing the influence of non-Gaussian noise. Consequently, the proposed filter is not only adaptive to unknown measurement noise statistics but also robust to random measurement delays and non-Gaussian noise. Finally, the MRD-VBAHCHF is verified for use in inertial navigation system/visual navigation system (INS/VNS) integrated navigation on asteroid missions, and the results of Monte Carlo simulations demonstrate that the MRD-VBAHCHF outperforms the high-degree cubature Kalman filter (HCKF), the MRD-HCKF and the variational Bayesian adaptive high-degree cubature Huber-based filter (VBAHCHF), thus showing the superiority of the proposed filter.

A novel aptamer-based fluorescent-sensing platform with a triple-helix molecular switch (THMS) was proposed as a switch for detecting the arsenic(III) ion. The triple helix structure was prepared by binding a signal transduction probe and arsenic aptamer. Additionally, the signal transduction probe labeled with fluorophore (FAM) and quencher (BHQ1) was employed as a signal indicator. The proposed aptasensor is rapid, simple and sensitive, with a limit of detection of 69.95 nM. The decrease in peak fluorescence intensity shows a linear dependence, with the concentration of As(III) in the range of 0.1 µM to 2.5 µM. The whole detection process takes 30 min. Moreover, the THMS-based aptasensor was also successfully used to detect As(III) in a real sample of Huangpu River water with good recoveries. The aptamer-based THMS also presents distinct advantages in stability and selectivity. The proposed strategy developed herein can be extensively applied in the field of food inspection.

In this paper, an improved extended state observer (ESO) based on sigmoid function and a finite-time convergence attitude controller are designed for reusable launch vehicle (RLV) in the re-entry phase. First, a control-oriented model (COM) of the RLV is established. According to the singular perturbation theory, the RLV control system is divided into an outer-loop and inner-loop subsystems. Second, a sigmoid function ESO (SESO) is proposed to estimate the model uncertainties and external disturbance caused by the large attitude maneuver and complicated external environment during the RLV re-entry phase. The continuous differentiable sigmoid function has the significant ability in noise suppression. By selecting the proper Lyapunov function, the stability of the SESO is proved. Then, based on the sliding mode control (SMC) theory, an improved multivariable super-twisting high-order sliding mode controller is designed. The finite-time convergence for the whole system is proven by the Lyapunov function technology. Finally, a 6-degree-of-freedom (6-DOF) RLV model is utilized to simulate to verify the effectiveness and robustness of the proposed control scheme.

Summary: Crohn’s disease (CD) is a kind of refractory intestinal inflammatory diseases. Pyroptosis was recently identified as a gasdermin-mediated proinflammatory cell death. However, it is unclear whether gasdermin-mediated pyroptosis participates in the pathogenesis of CD. Here, we show that the pyroptosis-inducing fragment GSDME N-terminal is obviously detected in the inflamed colonic mucosa but not in the uninflamed mucosa of patients with CD, suggesting that GSDME-mediated pyroptosis may be correlated with intestinal mucosal inflammation in CD. To investigate the role of GSDME in colitis development, Gsdme−/− mice and wild-type (WT) littermate controls were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. We found that Gsdme−/− mice exhibit less-severe intestinal inflammation than WT controls do. Furthermore, our results indicate that GSDME-mediated epithelial-cell pyroptosis induces intestinal inflammation through the release of proinflammatory intracellular contents. In summary, we show that GSDME participates in the pathogenesis of CD through GSDME-mediated pyroptosis to release proinflammatory cytokines.

Based on the characteristics of aero surfaces and reaction control system (RCS), a control allocation scheme is needed to specify aero surface deflections and RCS thruster’s firing commands, during the re-entry phase of reusable launch vehicle (RLV). To analyze the control performance differences introduced by different allocation algorithms, this paper presents a proportional allocation scheme based on dynamic pressure, a daisy-chaining allocation scheme based on the control error, and a multi-object-based optimal allocation scheme, to deal with the allocation problem of RCS and aero surfaces. The first allocation scheme is the simplest, and the second one is more complicated, when considering the actuators’ physical constraints in the allocation problem. The third scheme not only takes the physical constraints into account, but also the rate constraints, and other constraints of RCS and aero surfaces, while for the objective optimization function, not like the single-object function of the other two schemes, it combines the allocation error minimization, fuel consumption minimization, and other functions, with the adaptive weight values. After the stability analysis, the feasibility of the aforementioned allocation schemes are verified by the simulation, and the contrastive analysis of their control performances are followed.

Background Non-suicidal self-injury (NSSI) is a frequent and prominent phenomenon in major depressive disorder (MDD). Even though its prevalence and risk factors are relatively well understood, the potential mechanisms of NSSI in MDD remain elusive. Aims To review present evidence related to the potential mechanisms of NSSI in MDD. Methods According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, articles for this systematic review were searched on Medline (through PubMed), Embase (through Elsevier), PsycINFO (through OVID) and Web of Science databases for English articles, as well as China National Knowledge Infrastructure (CNKI), SinoMed, Wanfang Data, and the Chongqing VIP Chinese Science and Technology Periodical (VIP) Databases for Chinese articles published from the date of inception to 2 August 2022. Two researchers (BW, HZ) independently screened studies based on inclusion and exclusion criteria and assessed their quality. Results A total of 25 157 studies were searched. Only 25 of them were ultimately included, containing 3336 subjects (1535 patients with MDD and NSSI, 1403 patients with MDD without NSSI and 398 HCs). Included studies were divided into 6 categories: psychosocial factors (11 studies), neuroimaging (8 studies), stress and hypothalamic-pituitary-adrenal (HPA) axis (2 studies), pain perception (1 study), electroencephalogram (EEG) (2 studies) and epigenetics (1 study). Conclusions This systematic review indicates that patients with MDD and NSSI might have specific psychosocial factors, aberrant brain functions and neurochemical metabolisms, HPA axis dysfunctions, abnormal pain perceptions and epigenetic alterations. [ABSTRACT FROM AUTHOR]

Steroidogenic acute regulatory protein (StAR) plays a critical role in the regulation of progesterone (P4) production. Resveratrol (RSV), a natural polyphenol, has beneficial effects on reproductive function. However, its effects on StAR expression and P4 production in human granulosa cells remain undetermined. In this study, we showed that treatment of RSV upregulated StAR expression in human granulosa cells. G protein-coupled estrogen receptor (GPER) and ERK1/2 signaling were involved in RSV-stimulated StAR expression and P4 production. In addition, the expression of a tran-scriptional repressor, Snail, was downregulated by RSV, which contributed to the RSV-induced inductions of StAR expression and P4 production. [ABSTRACT FROM AUTHOR]

During the development of the placenta, trophoblast cell invasion must be carefully regulated. Although EGF has been shown to promote trophoblast cell invasion, the underlying mechanism remains largely undetermined. Our previous study using RNA-sequencing (RNA-seq) has identified that kisspeptin-1 is a downstream target of EGF in a human trophoblast cell line, HTR-8/SVneo, and mediates EGF-stimulated cell invasion. In the present study, after re-analysis of our previous RNA-seq data, we found that the CTGF was also downregulated in response to the EGF treatment. The inhibitory effects of EGF on CTGF mRNA and protein levels were confirmed in HTR-8/SVneo cells by reverse transcription quantitative real-time PCR and western blot, respectively. Treatment with EGF activated both PI3K/AKT and ERK1/2 signaling pathways. Using pharmacological inhibitors, our results showed that EGFR-mediated activation of PI3K/AKT signaling was required for the EGF-downregulated CTGF mRNA and protein levels. Matrigel-coated transwell invasion assays demonstrated that EGF treatment stimulated cell invasion. In addition, the invasiveness of HTR-8/SVneo cells was suppressed by treatment with recombinant human CTGF. By contrast, siRNA-mediated knockdown of CTGF increased cell invasion. Notably, the EGF-promoted HTR-8/SVneo cell invasion was attenuated by co-treatment with CTGF. This study provides important insights into the molecular mechanisms mediating EGF-stimulated human trophoblast cell invasion and increases the understanding of the biological functions of CTGF in the human placenta. [ABSTRACT FROM AUTHOR]

This paper studies the feasibility of the single-stage-to-orbit (SSTO) rocket with an initial nonzero velocity given by the auxiliary electromagnetic launch (EML) system. First, the development history of the SSTO rocket is sketched. Then, on the basis of Ziolkovsky formula, the preliminary feasibility analysis of SSTO rockets is proposed, which is very helpful to draw the boundary of feasible SSTO rockets' payload ratios, and shows the difficulty of SSTO without the initial velocity. Furthermore, deriving from the rocket's dynamic model in the longitudinal plane, a theoretical relationship function between the initial velocity and the maximum payload ratio of SSTO rockets is emphatically researched. Then, taking some typical SSTO rockets' prototypes or demonstrators as example, based on the corresponding trajectory simulations of their nonlinear dynamic models, the initial velocities for the feasible SSTO scheme are achieved under different maximum payload ratios. Finally, the conclusion is presented by analyzing the simulation results of the aforementioned study, and the application scope of SSTO rockets with EML technology is introduced in the terms of the mission feasibility and economics. [ABSTRACT FROM AUTHOR]