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Abstract Background Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN. Methods Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected. Results CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs. Conclusions CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.

Investigation on long-term effects of robot-assisted poststroke rehabilitation is challenging because of the difficulties in administration and follow-up of individuals throughout the process. A mobile hybrid neuromuscular electrical stimulation (NMES)-robot, i.e., exoneuromusculoskeleton (ENSM) was adopted for a single-group trial to investigate the long-term effects of the robot-assisted self-help telerehabilitation on upper limb motor function after stroke. Twenty-two patients with chronic stroke were recruited to attend a 20-session telerehabilitation program assisted by the wrist/hand module of the ENMS (WH-ENMS). Participants were evaluated before, after, as well as at 3 months and 6 months after the training. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), supplemented by secondary outcome measures of the FMA-UE of the shoulder and elbow (FMA shoulder/elbow), the FMA-UE of the wrist and hand (FMA wrist/hand), the Modified Ashworth Scale (MAS), the Action Research Arm Test (ARAT), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM), as well as electromyography (EMG) and kinematic measurements. Twenty participants completed the telerehabilitation program, with 19 returning for a 3-month follow-up, and 18 for a 6-month follow-up. Significantly improved clinical scores were observed after the training (p ≤ 0.05). These improvements were maintained after 6 months in the FMA-UE, FMA shoulder/elbow, MAS at the wrist flexor, WMFT score, WMFT time, and FIM (p ≤ 0.05). The maintained improvements in motor function were attributed to reduced muscular compensation, as indicated by EMG and kinematic parameters. The WH-ENMS-assisted self-help telerehabilitation could achieve long-lasting rehabilitative effects in chronic stroke.

Background: Trans-spinal electrical stimulation (tsES) to the intact spinal cord poststroke may modulate the cortico-muscular control in stroke survivors with diverse lesions in the brain. This work aimed to investigate the immediate effects of tsES on the cortico-muscular descending patterns during voluntary upper extremity (UE) muscle contractions by analyzing cortico-muscular coherence (CMCoh) and electromyography (EMG) in people with chronic stroke.Methods: Twelve chronic stroke participants were recruited to perform wrist-hand extension and flexion tasks at submaximal levels of voluntary contraction for the corresponding agonist flexors and extensors. During the tasks, the tsES was delivered to the cervical spinal cord with rectangular biphasic pulses. Electroencephalography (EEG) data were collected from the sensorimotor cortex, and the EMG data were recorded from both distal and proximal UE muscles. The CMCoh, laterality index (LI) of the peak CMCoh, and EMG activation level parameters under both non-tsES and tsES conditions were compared to evaluate the immediate effects of tsES on the cortico-muscular descending pathway.Results: The CMCoh and LI of peak CMCoh in the agonist distal muscles showed significant increases (p < 0.05) during the wrist-hand extension and flexion tasks with the application of tsES. The EMG activation levels of the antagonist distal muscle during wrist-hand extension were significantly decreased (p < 0.05) with tsES. Additionally, the proximal UE muscles exhibited significant decreases (p < 0.05) in peak CMCoh and EMG activation levels by applying tsES. There was a significant increase (p < 0.05) in LI of peak CMCoh of proximal UE muscles during tsES.Conclusion: The cervical spinal cord neuromodulation via tsES enhanced the residual descending excitatory control, activated the local inhibitory circuits within the spinal cord, and reduced the cortical and proximal muscular compensatory effects. These results suggested the potential of tsES as a supplementary input for improving UE motor functions in stroke rehabilitation.

Stroke rehabilitation, which demands consistent, intensive, and adaptable intervention in the long term, faced significant challenges due to the COVID-19 pandemic. During this time, telerehabilitation emerged as a noteworthy complement to traditional rehabilitation services, offering the convenience of at-home care delivery and overcoming geographical and resource limitations. Self-help rehabilitation robots deliver repetitive and intensive physical assistance, thereby alleviating the labor burden. However, robots have rarely demonstrated long-term readiness for poststroke telerehabilitation services. The transition from research trials to general clinical services presents several challenges that may undermine the rehabilitative gains observed in these studies. This perspective discusses the technological readiness of personal use robots in the context of telerehabilitation and identifies the potential challenges for their clinical translation. The goal is to leverage technology to seamlessly integrate it into standard clinical workflows, ultimately enhancing the outcomes of stroke rehabilitation.

The adversarial risk of a machine learning model has been widely studied. Most previous studies assume that the data lie in the whole ambient space. We propose to take a new angle and take the manifold assumption into consideration. Assuming data lie in a manifold, we investigate two new types of adversarial risk, the normal adversarial risk due to perturbation along normal direction and the in-manifold adversarial risk due to perturbation within the manifold. We prove that the classic adversarial risk can be bounded from both sides using the normal and in-manifold adversarial risks. We also show a surprisingly pessimistic case that the standard adversarial risk can be non-zero even when both normal and in-manifold adversarial risks are zero. We finalize the study with empirical studies supporting our theoretical results. Our results suggest the possibility of improving the robustness of a classifier without sacrificing model accuracy, by only focusing on the normal adversarial risk.

ABSTRACT Group B Streptococcus (GBS) remains the leading cause of serious neonatal infection. Prenatal screening for vaginal and rectal GBS colonization is necessary in late pregnancy. Our objective was to compare the performance of four methods including the Xpert Xpress GBS, standard broth enrichment culture, real-time quantitative PCR (qPCR), and direct culture, for detecting of GBS in rectovaginal specimens. Among 939 pregnant women at 35–37 weeks of gestation recruited in the study, 168 (17.9%) were determined to be GBS-colonized by broth enrichment culture, the gold standard. The sensitivity and specificity of the Xpert Xpress GBS were 94.6% and 95.9%, respectively. The hands-on time and running time of the Xpert Xpress GBS were 1 minute and less than 1 hour, respectively. As a random-access, integrated device, the Xpert Xpress GBS test efficiently and accurately screens rectovaginal swabs for GBS colonization in pregnant women. IMPORTANCE This was the first study evaluating the performance of the Xpert Xpress group B Streptococcus (GBS) test using rectovaginal swabs from Chinese pregnant women. Compared to the other three assays, the Xpert Xpress GBS test demonstrated high sensitivity and specificity when screening 939 pregnant women for GBS in rectovaginal specimens. Additionally, its reduced time to obtain results makes it valuable for the rapid detection of GBS.

γδ T cells play a critical role in homeostasis and diseases such as infectious diseases and tumors in both mice and humans. They can be categorized into two main functional subsets: IFN-γ-producing γδT1 cells and IL-17-producing γδT17 cells. While CD27 expression segregates these two subsets in mice, little is known about human γδT17 cell differentiation and expansion. Previous studies have identified γδT17 cells in human skin and mucosal tissues, including the oral cavity and colon. However, human γδ T cells from peripheral blood mononuclear cells (PBMCs) primarily produce IFN-γ. In this protocol, we describe a method for in vitro expansion and polarization of human γδT17 cells from PBMCs.Key Features• Expansion of γδ T cells from peripheral blood mononuclear cells.• Human IL-17A-producing γδ T-cell differentiation and expansion using IL-7 and anti-γδTCR.• Analysis of IL-17A production post γδ T-cell expansion.

Post-stroke depression (PSD) has negative impacts on the daily life of stroke survivors and delays their neurological recovery. However, traditional post-stroke rehabilitation mainly focused on motor restoration, whereas little attention was given to the affective deficits. Effective management of PSD, including diagnosis, intervention, and follow-ups, is essential for post-stroke rehabilitation. As an objective measurement of the nervous system, electroencephalography (EEG) has been applied to the diagnosis and evaluation of PSD. In this paper, we reviewed the literature most related to the clinical applications of EEG for PSD and offered a cross-section that is useful for selecting appropriate approaches in practice. This study aimed to gather EEG-based empirical evidence for PSD diagnosis, review interventions for managing PSD, and analyze the evaluation approaches. In total, 33 diagnostic studies and 19 intervention studies related to PSD and depression were selected from the literature. It was found that the EEG features analyzed by both band-based and nonlinear dynamic approaches were capable of quantifying the abnormal neural responses on the cortical level for PSD diagnosis and intervention evaluation/prediction. Meanwhile, EEG-based machine learning has also been applied to the diagnosis and evaluation of depression to automate and speed up the process, and the results have been promising. Although brain-computer interface (BCI) interventions have been widely applied to post-stroke motor rehabilitation and cognitive training, BCI emotional training has not been directly used in PSD yet. This review showed the need for understanding the cortical responses of PSD to improve its diagnosis and precision treatment. It also revealed that future post-stroke rehabilitation plans should include training sessions for motor, affect, and cognitive functions and closely monitor their improvements.

Traditional animal pose estimation techniques based on images face significant hurdles, including scarce training data, costly data annotation, and challenges posed by non-rigid deformation. Addressing these issues, we proposed dynamic conditional prompts for the prior knowledge of animal poses in language modalities. Then, we utilized a multimodal (language–image) collaborative training and contrastive learning model to estimate animal poses. Our method leverages text prompt templates and image feature conditional tokens to construct dynamic conditional prompts that integrate rich linguistic prior knowledge in depth. The text prompts highlight key points and relevant descriptions of animal poses, enhancing their representation in the learning process. Meanwhile, transformed via a fully connected non-linear network, image feature conditional tokens efficiently embed the image features into these prompts. The resultant context vector, derived from the fusion of the text prompt template and the image feature conditional token, generates a dynamic conditional prompt for each input sample. By utilizing a contrastive language–image pre-training model, our approach effectively synchronizes and strengthens the training interactions between image and text features, resulting in an improvement to the precision of key-point localization and overall animal pose estimation accuracy. The experimental results show that language–image contrastive learning based on dynamic conditional prompts enhances the average accuracy of animal pose estimation on the AP-10K and Animal Pose datasets.

Abstract Background: Grain size is a direct determinant of grain weight and yield in rice; however, the genetic and molecular mechanisms determining grain size remain largely unknown. Findings: We identified a mutant, wide grain 3 (wg3), which exhibited significantly increased grain width and 1000-grain weight. Cytological analysis showed that WG3 regulates grain size by affecting cell proliferation. MutMap-based gene cloning and a transgenic experiment demonstrated that WG3 encodes a GRAS protein. Moreover, we found that WG3 directly interacts with DWARF AND LOW-TILLERING (DLT), a previously reported GRAS protein, and a genetic experiment demonstrated that WG3 and DLT function in a common pathway to regulate grain size. Additionally, a brassinosteroid (BR) sensitivity test suggested that WG3 has a positive role in BR signaling in rice. Collectively, our results reveal a new genetic and molecular mechanism for the regulation of grain size in rice by the WG3-DLT complex, and highlight the important functions of the GRAS protein complex in plants. Conclusion: WG3 functions directly in regulating grain size and BR signaling in rice.

The sand body structure and geochemical characteristics of braided river reservoirs are the key geological factors affecting gas production and development effects. The Sulige gas field in the Ordos Basin is an important large-scale gas-producing layer. Owing to the control of sedimentary facies, the geological structure of the sand body changes greatly and its connectivity is poor. The geological characteristics have not yet been elucidated, and this is an important problem restricting the development of the Sulige Gas Field. To solve this problem, this study focuses on the braided river reservoir of the Shihezi Formation in Block 19 of the Sulige Gas Field, conducts geological surveys in the study area, analyzes the geological and geochemical characteristics of the reservoir, and obtains samples through drilling. Through a thin-section test, gas-water two-phase experiment, and simulation test, the braided river reservoir configuration and pore and gas-water characteristics are obtained. The results show that the reservoir lithology in the study area is mainly composed of quartz sandstone, lithic sandstone, and quartzy lithic sandstone, with a porosity of 3%–13% and a permeability of (0.05–0.7) × 10−3 m2. The reservoir has low porosity and low permeability. After drilling samples were obtained, 32 thin-section rock samples were selected. The pore types of the block reservoir mainly (82.9%) consisted of intragranular and intergranular dissolved pores. The difference in pore structure was mainly reflected by the size and distribution of the throat. The distribution of physical properties was 6%–10%, the gas saturation was 61%, the NMR effective porosity was 7.49%, the permeability was 4.08 × 102 μm2, and the physical properties were relatively good. In terms of the study area, the average thickness of the single braided channel in the lower section of He 8 was 4.7 m, the average width of the channel was 963 m, and the composite channel was distributed in a potato shape, parallel to the direction of the main flow. The average length of the channel was 2,147 m and the average width was 844 m. As the porosity increased, the efficiency of gas-driven water also increased, and there was a linear positive correlation between porosity and gas-driven water efficiency. With the increase in movable water saturation, the water-air ratio became larger and water production was greater. In low-amplitude structures and under low-permeability background conditions, for reservoirs with good local pore structure and physical properties, the water remaining at the bottom of the reservoir or sand body was controlled by the accumulation conditions or the weak structural differentiation after accumulation. In terms of the gas and water produced simultaneously in the study area, gas production was less than 2 × 104 m3/d and water production was relatively large at more than 10 m3/d; gas and water were mainly distributed in the downdip part of the main channel structure or in the island lens-shaped permeable sand bodies trapped by the surrounding tight layers. The study results provide theoretical data support for the exploration and production of the Sulige Gas Field.

Integrated sensing and communication (ISAC) is the dominant trend of the sixth generation mobile communication networks (6G).The introduction of ISAC into the reconfigurable intelligent surface (RIS) system can expand the system coverage, improve both communication and sensing performances, and reduce the hardware cost as well as the power consumption of the system.On the basis of outlining and analyzing the research status of ISAC in RIS systems, two non-orthogonal ISAC methods were proposed to support concurrent communication and sensing for blind-zone users on non-orthogonal time-frequency resources.Finally, the technical challenges and future development of ISAC in RIS systems were discussed.

Focal vibratory stimulation (FVS) and neuromuscular electrical stimulation (NMES) are promising technologies for sensory rehabilitation after stroke. However, the differences between these techniques in immediate neuromodulatory effects on the poststroke cortex are not yet fully understood. In this research, cortical responses in persons with chronic stroke (n = 15) and unimpaired controls (n = 15) were measured by whole-brain electroencephalography (EEG) when FVS and NMES at different intensities were applied transcutaneously to the forearm muscles. Both FVS and sensory-level NMES induced alpha and beta oscillations in the sensorimotor cortex after stroke, significantly exceeding baseline levels (p < 0.05). These oscillations exhibited bilateral sensory deficiency, early adaptation, and contralesional compensation compared to the control group. FVS resulted in a significantly faster P300 response (p < 0.05) and higher theta oscillation (p < 0.05) compared to NMES. The beta desynchronization over the contralesional frontal–parietal area remained during NMES (p > 0.05), but it was significantly weakened during FVS (p < 0.05) after stroke. The results indicated that both FVS and NMES effectively activated the sensorimotor cortex after stroke. However, FVS was particularly effective in eliciting transient involuntary attention, while NMES primarily fostered the cortical responses of the targeted muscles in the contralesional motor cortex.

Abstract Family with sequence similarity 84, member B (FAM84B) is a significant copy number amplification gene in the 8q24.21 locus identified by our previous WGS study in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance and potential mechanisms have been elusive. Here, we performed the association analyses between FAM84BAmp and clinicopathological features using 507 ESCC samples. The results indicated that, compared with the FAM84Bnon-Amp patients, the FAM84BAmp patients showed a more aggressive and a worse prognosis. A significant correlation was discovered between the expression level of FAM84B and FAM84BAmp in the ESCC cohort. Furthermore, we found that the forced expression change of FAM84B can influence ESCC cell proliferation and cell-cycle status, which is probably mediated by NPM1. A direct interaction between FAM84B and the C-terminal (189–294aa) of NPM1 was identified, which increased the NPM1 nuclear expression. Over-expression of NPM1 could inhibit the CDKN2A protein expression, which might affect the ESCC cell cycle. Our results indicate FAM84B CNA may be a potential diagnostic and therapeutic biomarker in ESCC, meanwhile, reveal a novel mechanism of FAM84B that promotes tumorigenesis via interacting with NPM1 and suppressing CDKN2A.

Summary: Natural IL-17-producing γδ T cells (γδT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of γδT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of γδT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult γδT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential (ΔΨm) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues γδT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in γδT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and γδT17 thymic programming and functional acquisition.

Several preclinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multidose gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy-induced reactive myelopoiesis biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM-treated BM Lin−Sca1+c-Kit+ cells and monocytes. Treatment with the mitochondria targeted antioxidant abrogated GEM-induced hyperdifferentiation of BM progenitors. In addition, GEM treatment induced upregulation of host cell–derived CCL2, and knockout of CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced the pro-metastatic effect of chemotherapy. Together, these studies suggest a potentially novel mechanism for chemotherapy-induced metastasis via the host response–induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.

Background Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.Methods β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag−/− mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.Results IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.Conclusions These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.

Abstract Background P16INK4A is a surrogate signature compensating for the specificity and/or sensitivity deficiencies of the human papillomavirus (HPV) DNA and Papanicolaou smear (Pap) co‐test for detecting high‐grade cervical squamous intraepithelial lesions or worse (HSIL+). However, traditional p16INK4A immunostaining is labour intensive and skill demanding, and subjective biases cannot be avoided. Herein, we created a high‐throughput, quantitative diagnostic device, p16INK4A flow cytometry (FCM) and assessed its performances in cervical cancer screening and prevention. Methods P16INK4A FCM was built upon a novel antibody clone and a series of positive and negative (p16INK4A‐knockout) standards. Since 2018, 24 100‐women (HPV‐positive/‐negative, Pap‐normal/‐abnormal) have been enrolled nationwide for two‐tier validation work. In cross‐sectional studies, age‐ and viral genotype‐dependent expression of p16INK4A was investigated, and optimal diagnostic parameter cut‐offs (using colposcopy and biopsy as a gold standard) were obtained. In cohort studies, the 2‐year prognostic values of p16INK4A were investigated with other risk factors by multivariate regression analyses in three cervicopathological conditions: HPV‐positive Pap‐normal, Pap‐abnormal biopsy‐negative and biopsy‐confirmed LSIL. Results P16INK4A FCM detected a minimal ratio of 0.01% positive cells. The p16INK4A‐positive ratio was 13.9 ± 1.8% among HPV‐negative NILM women and peaked at the ages of 40–49 years; after HPV infection, the ratio increased to 15.1 ± 1.6%, varying with the carcinogenesis of the viral genotype. Further increments were found in women with neoplastic lesions (HPV‐negative: 17.7 ± 5.0–21.4 ± 7.2%; HPV‐positive: 18.0 ± 5.2–20.0 ± 9.9%). Extremely low expression of p16INK4A was observed in women with HSILs. As the HPV‐combined double‐cut‐off‐ratio criterion was adopted, a Youden's index of 0.78 was obtained, which was significantly higher than that (0.72) of the HPV and Pap co‐test. The p16INK4A‐abnormal situation was an independent HSIL+ risk factor for 2‐year outcomes in all three cervicopathological conditions investigated (hazard ratios: 4.3–7.2). Conclusions FCM‐based p16INK4A quantification offers a better choice for conveniently and precisely monitoring the occurrence of HSIL+ and directing risk‐stratification‐based interventions.