Robust Prescribed Performance Control of Nonlinear Systems With Unknown Odd Powers.

This article is concerned with the problem of reference tracking for the lower-triangular nonlinear systems with a chain of odd powers. Contrary to most of the related studies, this work is focused on the case where neither the odd powers nor their bounds are known. This renders the majority of the existing methods for stability analysis and control design for the odd-power systems infeasible. To surmount this challenge, a robust prescribed performance control strategy together with a constraint analysis by contradiction is put forward. Instead of the well-established adding one power integrator technique, a group of barrier functions are employed to combat the tracking error and the intermediate errors. In lieu of the Lyapunov stability theory, a constraint analysis by contradiction is carried out, which discloses the inherent robustness of the control system against the nonparametric uncertainties, the unmatched disturbances and the unknown odd powers. It is guaranteed that the tracking error enters into a preassigned neighborhood of zero after a given time, with a predefined bound on the overshoot. In addition, the proposed control exhibits a striking simplicity. Despite the severe model uncertainties and the recursive control design, no effort needs to be paid for parameter identification, function approximation, disturbance estimation, or derivative calculation. The above theoretical findings are substantiated by the comparative simulation results.

Radix Astragali and Its Representative Extracts for Diabetic Nephropathy: Efficacy and Molecular Mechanism.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM). Radix Astragali (RA), a frequently used Chinese herbal medicine in the Leguminosae family, Astragalus genus, with its extracts, has been proven to be effective in DN treatment both in clinical practice and experimental studies. RA and its extracts can reduce proteinuria and improve renal function. They can improve histopathology changes including thickening of the glomerular basement membrane, mesangial cell proliferation, and injury of endothelial cells, podocytes, and renal tubule cells. The mechanisms mainly benefited from antioxidative stress which involves Nrf2/ARE signaling and the PPARγ-Klotho-FoxO1 axis; antiendoplasmic reticulum stress which involves PERK-ATF4-CHOP, PERK/eIF2α, and IRE1/XBP1 pathways; regulating autophagy which involves SIRT1/NF-κB signaling and AMPK signaling; anti-inflammation which involves IL33/ST2 and NF-κB signaling; and antifibrosis which involves TGF-ß1/Smads, MAPK (ERK), p38/MAPK, JNK/MAPK, Wnt/ß-catenin, and PI3K/AKT/mTOR signaling pathways. This review focuses on the clinical efficacy and the pharmacological mechanism of RA and its representative extracts on DN, and we further document the traditional uses of RA and probe into the TCM theoretical basis for its application in DN.

The Effective Separation of Gallium, Vanadium, and Aluminum from a Simulated Bayer Solution by Resin Exchange.

The effective recovery of gallium from wastewater discharge in the Bayer process is promising for the long-term development of gallium resources. The adsorption and desorption behavior of gallium (Ga), vanadium (V), and aluminum (Al) ions on a strong acidic styrene cation exchange resin (JK resin) from a simulated Bayer solution was systematically investigated by static experiments. The results showed that the optimum conditions for separating Ga from V and Al were at low temperatures and short contact times, with 78.30%, 15.16%, and 6.63% of the adsorption efficiency at 25 °C and 60 min, respectively, for Ga, V, and Al. The adsorption kinetics of Ga3+ conformed to the pseudo-second order model, and the static saturation adsorption capacity was 18.25 mg/g. The Langmuir model fitted the adsorption isotherm of gallium well, and the maximum adsorption capacity was 1.11 mg/g at 25 °C. FT-IR spectroscopy and XPS showed that the mechanism of the Ga3+ adsorption was only related to the interaction of the oxygen atoms of the amide oxime group (C=NOH). The separation of Ga, V, and Al can be achieved by desorbing 98% of Al with low concentrations of ammonia and 90% of Ga with low concentrations of hydrochloric acid. The results indicate that JK resin is an efficient adsorbent for separating gallium and vanadium in alkaline solutions.

Current trends in digital replantation-a narrative review.

Background and Objective: Digital replantation for traumatic amputation has become the standard of care with advances in microsurgical techniques and technology. While digital replantation has progressed significantly, there are still gaps in knowledge in many aspects. Some of the controversial topics in digital replantation include the indications and contraindications, anesthesia, number of vessel anastomoses, mechanism of injury, role of vein graft, distal fingertip replantation, and postoperative management. This article is a narrative review that discusses these controversies and current issues pertaining to digital replantation. Methods: PubMed, Web of Science, and Google scholar were searched using keywords relating to "digit replantation", "amputation", and "digital replant" with the following terms: "indications", "contraindications", "anaesthesia", "survival", "vessels", "mechanism of injury", "vein graft", "outcome", and "thrombophylaxis". Relevant articles pertaining to digital replantation and deemed by the authors as current or controversial were included. Key Content and Findings: The reported survival rates of digital replantation are high. With the advancement of microsurgical techniques and technology, the boundaries of digital replantation continue to be pushed. Various methods have been described recently to improve the success rates of difficult replants, such as strategies for venous outflow and vein grafting. However, there are still aspects of digital replantation that remain unanswered, such as the number of veins to anastomose and the thromboprophylaxis regime. Conclusions: The review delves into controversial aspects of digital replantation, including contraindications, anesthesia, and postoperative management. Indications and contraindications will continue to evolve alongside advancements in microsurgical techniques and anesthesia. It highlights key factors influencing survival rates, such as the number of repaired vessels and the mechanism of injury. Finally, the review consolidates strategies for managing challenging digital replantations.

Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies.

HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. Here, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%), had a poor response to current anti-HER2 dual-targeted therapies and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment.

Identification of novel Tet(X6)-Tet(X2) recombinant variant in Elizabethkingia meningoseptica from a bullfrog farm and downstream river in China.

Introduction: The dissemination of strains producing tetracyclines monooxygenase Tet(X) from breeding farms to the natural environment poses a potential threat to public health. Methods: Antimicrobial susceptibility testing and WGS were performed to identify resistance phenotypes and genotypes. Cloning experiments, sequence alignment, and homology modeling were used to characterize the function and formation mechanisms of the recombinant variant. The mobilization potential of Tet(X) was assessed by collinearity analysis, conjugation experiments, and phylogenetic analysis. Results: Three tet(X)-producing Elizabethkingia meningoseptica strains were isolated from bullfrog breeding ponds, the sewage outlet, and downstream river in Zhejiang Province, China. These strains carry a novel Tet(X) variant, differing from Tet(X6) by seven residues, and possess the ability to degrade tetracyclines. Interestingly, the novel Tet(X) is a recombinant variant formed by homologous recombination of Tet(X6) and the C-terminal of Tet(X2). Further analysis revealed that Tet(X6) formed several Tet(X) variants, including Tet(X5), through homologous recombination. The novel tet(X) gene is located on a circularizable integrative and conjugative element (ICEEmeChn3), with ISwz1 participating in the recombination of its multi-drug resistance region, potentially facilitating the mobilization and recombination of tet(X) in early hosts. These three strains were clonally transmitted and shared a close genetic relationship (SNP < 62) with a clinically-sourced strain isolated from the same province. Discussion: To our knowledge, this is the first report of homologous recombination between Tet(X) variants with differing activities. These clonal strains provide evidence of the transmission of tet(X)-positive strains from aquaculture sewage to the natural environment, highlighting the need to strengthen the monitoring and management of this emerging farming model.

Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.

Exploring the Health Benefits of Boletus aereus Polysaccharides: Extraction, Structural Characterization, and Antiproliferative Properties against Non-Hodgkin's Lymphomas (NHLs).

Boletus aereus Fr. ex Bull. stands out as a delectable edible mushroom with high nutritional and medicinal values, featuring polysaccharides as its primary nutrient composition. In our continuous exploration of its beneficial substances, a novel polysaccharide (BAPN-1) with a molecular weight of 2279 kDa was prepared. It was identified as a glucan with a backbone composed of the residues →4)-α-Glcp-(1→ and →4,6)-α-Glcp-(1→ connected in a proportion of 5:1 and a ß-Glcp-(1→ side residue attached at C6 of the →4,6)-α-Glcp-(1→ residue. Biologically, BAPN-1 exhibited broad-spectrum antiproliferative activities against various NHL cells, including HuT-78, OCI-LY1, OCI-LY18, Jurkat, RL, and Karpas-299, with IC50 values of 0.73, 1.21, 3.18, 1.52, 3.34, and 4.25 mg/mL, respectively. Additionally, BAPN-1 significantly induced cell cycle arrest in the G2/M phase and caused apoptosis of NHL cells. Mechanistically, bulk RNA sequencing and Western blot analysis revealed that BAPN-1 could upregulate cyclin B1 and enhance cleaved caspase-9 expression through the inhibition of FGFR3 and RAF-MEK-ERK signaling pathways. This work supports the improved utilization of B. aereus in high-value health products.

Construction and validation of prognostic signature for transcription factors regulating T cell exhaustion in hepatocellular carcinoma.

In the tumor microenvironment (TME), CD8+ T cells showed stage exhaustion due to the continuous stimulation of tumor antigens. To evaluate the status of CD8+ T cells and reverse the exhaustion is the key to evaluate the prognosis and therapeutic effect of tumor patients. The aim of this study was to establish a prognostic signature that could effectively predict prognosis and response to immunotherapy in patients with hepatocellular carcinoma (HCC). We used univariate Cox analysis to obtain transcription factors associated with CD8+ T cell exhaustion from The Cancer Genome Atlas dataset. Then, the prognostic signature for transcription factors basic leucine zipper ATF-like transcription factor, Eomesodermin, and T-box protein 21 regulating T cell exhaustion was constructed using LASSO Cox regression. The relative expression levels of the mRNA of the 3 transcription factors were detected by reverse transcription-quantitative polymerase chain reaction in 23 pairs of HCC and paracancer tissues, and verified internally in The Cancer Genome Atlas dataset and externally in the International Cancer Genome Consortium dataset. Cox regression analysis showed that risk score was an independent prognostic variable. The overall survival of the high-risk group was significantly lower than that of the low-risk group. The low-risk group had higher immune scores, matrix scores, and ESTIMATE scores, and significantly increased expression levels of most immune checkpoint genes in the low-risk group. Therefore, patients with lower risk scores benefit more from immunotherapy. The combination of the 3 transcription factors can evaluate the exhaustion state of CD8+ T cells in the TME, laying a foundation for evaluating the TME and immunotherapy efficacy in patients with HCC.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

Targeting transposable elements in cancer: developments and opportunities.

Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research.

Homeostatic regulation of rapid eye movement sleep by the preoptic area of the hypothalamus.

Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2→TMN neurons) are crucial for the homeostatic regulation of REMs in mice. POAGAD2→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs.

Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis.

BACKGROUND: Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. METHODS: In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. RESULTS: Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD. CONCLUSIONS: In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.

The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus.

Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.

Stability and variability of molecular subtypes: comparative analysis of primary and metastatic triple-negative breast cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive cancer. Although our previous study classified primary TNBC into four subtypes, comprehensive longitudinal investigations are lacking. METHODS: We assembled a large-scale, real-world cohort comprised of 880 TNBC patients [465 early-stage TNBC (eTNBC) and 415 metastatic TNBC (mTNBC) patients] who were treated at Fudan University Shanghai Cancer Center. The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort. Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes. RESULTS: The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1% (47/465). The median overall survival (OS) in the mTNBC cohort was 27.2 months [95% confidence interval (CI), 24.4-30.2 months], which indicated a poor prognosis. The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed. Consistent molecular subtypes were maintained in 77.5% of the patients throughout disease progression with the mesenchymal-like (MES) subtype demonstrating a tendency for subtype transition and brain metastasis. Additionally, a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial. CONCLUSIONS: Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression. However, we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

Risk factors for nephrolithiasis formation: an umbrella review.

OBJECTIVE: Nephrolithiasis is prevalent and burdensome worldwide. At present, evidence on the risk factors for nephrolithiasis is unconsolidated and the associations remain uncertain. The authors systematically evaluate the robustness of the meta-analytic evidence and aid more reliable interpretations of the epidemiological relationships. METHODS: The authors conducted a comprehensive review of the meta-analyses, screened the included studies with the aid of the AMSTAR 2 evaluation tool, and then used R (4.1.1) software to perform data analysis to evaluate the association between candidate risk factors and kidney stones, and evaluated the credibility of the evidence of the association between risk factors and kidney stones according to the GRADE classification, and finally obtained the strength and effectiveness of the association. RESULTS: The authors finally included 17 meta-analyses regarding 46 risk factors, 34 of which (73.9%) showed statistically significant association with nephrolithiasis. Among the significant associations, the authors found that waist circumference, BMI, dietary intake and fructose intake were positively correlated with the occurrence and development of nephrolithiasis. Caffeine, dietary fiber and DASH-diet showed a tendency to reduce kidney stones. Interestingly, calcium supplementation, dietary calcium, and vitamin D, which are widely believed to be responsible for stone formation, made no difference or even reduced the risk of nephrolithiasis. CONCLUSIONS: The authors' study demonstrates the suggestive causal (central obesity, type 2 diabetes, gout, dietary sodium, fructose intake and higher temperatures) risk factors of nephrolithiasis. The authors also demonstrate the suggestive causal (coffee/alcohol/beer intake, dietary calcium and DASH-diet) protective factors of nephrolithiasis. To provide epidemiological basis for the treatment and prevention of nephrolithiasis.

Low-Complexity Tracking Control of Unknown Strict-Feedback Systems With Quantitative Performance Guarantees.

This article is concerned with the prescribed performance tracking control problem for the strict-feedback systems with unknown nonlinearities and unmatched disturbances. The challenge lies in the realization of a complete performance specification for trajectory tracking in the sense of quantitatively regulating the peak value, overshoot, settling time, and accuracy while ensuring that the initial condition holds naturally. To this end, an error transformation, equipped with a shifting function, is introduced and incorporated with a new-type barrier function. Then, a class of performance functions is exploited to quantify the settling times and steady-state bounds of the intermediate errors. Moreover, to improve the flexibility of formulating performance specifications for the tracking error, a pair of asymmetric performance boundaries are further designed. With their combination, a novel robust prescribed performance control (PPC) approach is proposed in this article. It not only achieves the quantitative performance guarantees but also preserves the unique simplicity of PPC, evading the needs for function approximation, parameter identification, disturbance estimation, derivative calculation, or command filtering. The above theoretical findings are confirmed via three simulation studies.