PSTNet: Enhanced Polyp Segmentation With Multi-Scale Alignment and Frequency Domain Integration.

Accurate segmentation of colorectal polyps in colonoscopy images is crucial for effective diagnosis and management of colorectal cancer (CRC). However, current deep learning-based methods primarily rely on fusing RGB information across multiple scales, leading to limitations in accurately identifying polyps due to restricted RGB domain information and challenges in feature misalignment during multi-scale aggregation. To address these limitations, we propose the Polyp Segmentation Network with Shunted Transformer (PSTNet), a novel approach that integrates both RGB and frequency domain cues present in the images. PSTNet comprises three key modules: the Frequency Characterization Attention Module (FCAM) for extracting frequency cues and capturing polyp characteristics, the Feature Supplementary Alignment Module (FSAM) for aligning semantic information and reducing misalignment noise, and the Cross Perception localization Module (CPM) for synergizing frequency cues with high-level semantics to achieve efficient polyp segmentation. Extensive experiments on challenging datasets demonstrate PSTNet's significant improvement in polyp segmentation accuracy across various metrics, consistently outperforming state-of-the-art methods. The integration of frequency domain cues and the novel architectural design of PSTNet contribute to advancing computer-assisted polyp segmentation, facilitating more accurate diagnosis and management of CRC. Our source code is available for reference at https://github.com/clearxu/PSTNet.

Dual Nickel- and Photoredox-Catalyzed Asymmetric Reductive Cross-Couplings: Just a Change of the Reduction System?

ConspectusIn recent years, nickel-catalyzed asymmetric coupling reactions have emerged as efficient methods for constructing chiral C(sp3) carbon centers. Numerous novel approaches have been reported to rapidly construct chiral carbon-carbon bonds through nickel-catalyzed asymmetric couplings between electrophiles and nucleophiles or asymmetric reductive cross-couplings of two different electrophiles. Building upon these advances, our group has been devoted to interrogating dual nickel- and photoredox-catalyzed asymmetric reductive cross-coupling reactions.In our endeavors over the past few years, we have successfully developed several dual Ni-/photoredox-catalyzed asymmetric reductive cross-coupling reactions involving organohalides. While some probably think that this system is just a change of the reduction system from traditional metal reductants to a photocatalysis system, a question that we also pondered at the beginning of our studies, both the achievable reaction types and mechanisms suggest a different conclusion: that this dual catalysis system has its own advantages in the chiral carbon-carbon bond formation. Even in certain asymmetric reactions where the photocatalysis regime functions only as a reducing system, the robust reducing capability of photocatalysts can effectively accelerate the regeneration of low-valent nickel species, thus expanding the selectable scope of chiral ligands. More importantly, in many transformations, besides reducing nickel catalysts, the photocatalysis system can also undertake the responsibility of alkyl radical formation, thereby establishing two coordinated, yet independent catalytic cycles. This catalytic mode has been proven to play a crucial role in achieving diverse asymmetric coupling reactions with great challenges.In this Account, we elucidate our understanding of this system based on our experience and findings. In the Introduction, we provide an overview of the main distinctions between this system and traditional Ni-catalyzed asymmetric reductive cross-couplings with metal reductants and the potential opportunities arising from these differences. Subsequently, we outline various chiral carbon-carbon bond-forming types obtained by this dual Ni/photoredox catalysis system and their mechanisms. In terms of chiral C(sp3)-C(sp2) bond formation, extensive discussion focuses on the asymmetric arylations of α-chloroboronates, α-trifluoromethyl alkyl bromides, α-bromophosphonates, and so on. In the realm of chiral C(sp3)-C(sp) bond formation, asymmetric alkynylations of α-bromophosphonates and α-trifluoromethyl alkyl bromides have been presented herein. Regarding C(sp3)-C(sp3) bond formation, we take the asymmetric alkylation of α-chloroboronates as a compelling example to illustrate the great efficiency of this dual catalysis system. This summary would enable a better grasp of the advantages of this dual catalysis system and clarify how the photocatalysis regime facilitates enantioselective transformations. We anticipate that this Account will offer valuable insights and contribute to the development of new methodologies in this field.

Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer characterized by metabolic reprogramming. Glutamine metabolism is pivotal in metabolic reprogramming, contributing to the significant heterogeneity observed in ccRCC. Consequently, developing prognostic markers associated with glutamine metabolism could enhance personalized treatment strategies for ccRCC patients. This study obtained RNA sequencing and clinical data from 763 ccRCC cases sourced from multiple databases. Consensus clustering of 74 glutamine metabolism related genes (GMRGs)- profiles stratified the patients into three clusters, each of which exhibited distinct prognosis, tumor microenvironment, and biological characteristics. Then, six genes (SMTNL2, MIOX, TMEM27, SLC16A12, HRH2, and SAA1) were identified by machine-learning algorithms to develop a predictive signature related to glutamine metabolism, termed as GMRScore. The GMRScore showed significant differences in clinical prognosis, expression profile of immune checkpoints, abundance of immune cells, and immunotherapy response of ccRCC patients. Besides, the nomogram incorporating the GMRScore and clinical features showed strong predictive performance in prognosis of ccRCC patients. ALDH18A1, one of the GRMGs, exhibited elevated expression level in ccRCC and was related to markedly poorer prognosis in the integrated cohort, validated by proteomic profiling of 232 ccRCC samples from Fudan University Shanghai Cancer Center (FUSCC). Conducting western blotting, CCK-8, transwell, and flow cytometry assays, we found the knockdown of ALDH18A1 in ccRCC significantly promoted apoptosis and inhibited proliferation, invasion, and epithelial-mesenchymal transition (EMT) in two human ccRCC cell lines (786-O and 769-P). In conclusion, we developed a glutamine metabolism-related prognostic signature in ccRCC, which is tightly linked to the tumor immune microenvironment and immunotherapy response, potentially facilitating precision therapy for ccRCC patients. Additionally, this study revealed the key role of ALDH18A1 in promoting ccRCC progression for the first time.

Learning manufacturing computer vision systems using tiny YOLOv4.

Implementing and deploying advanced technologies are principal in improving manufacturing processes, signifying a transformative stride in the industrial sector. Computer vision plays a crucial innovation role during this technological advancement, demonstrating broad applicability and profound impact across various industrial operations. This pivotal technology is not merely an additive enhancement but a revolutionary approach that redefines quality control, automation, and operational efficiency parameters in manufacturing landscapes. By integrating computer vision, industries are positioned to optimize their current processes significantly and spearhead innovations that could set new standards for future industrial endeavors. However, the integration of computer vision in these contexts necessitates comprehensive training programs for operators, given this advanced system's complexity and abstract nature. Historically, training modalities have grappled with the complexities of understanding concepts as advanced as computer vision. Despite these challenges, computer vision has recently surged to the forefront across various disciplines, attributed to its versatility and superior performance, often matching or exceeding the capabilities of other established technologies. Nonetheless, there is a noticeable knowledge gap among students, particularly in comprehending the application of Artificial Intelligence (AI) within Computer Vision. This disconnect underscores the need for an educational paradigm transcending traditional theoretical instruction. Cultivating a more practical understanding of the symbiotic relationship between AI and computer vision is essential. To address this, the current work proposes a project-based instructional approach to bridge the educational divide. This methodology will enable students to engage directly with the practical aspects of computer vision applications within AI. By guiding students through a hands-on project, they will learn how to effectively utilize a dataset, train an object detection model, and implement it within a microcomputer infrastructure. This immersive experience is intended to bolster theoretical knowledge and provide a practical understanding of deploying AI techniques within computer vision. The main goal is to equip students with a robust skill set that translates into practical acumen, preparing a competent workforce to navigate and innovate in the complex landscape of Industry 4.0. This approach emphasizes the criticality of adapting educational strategies to meet the evolving demands of advanced technological infrastructures. It ensures that emerging professionals are adept at harnessing the potential of transformative tools like computer vision in industrial settings.

An epilepsy-associated CILK1 variant compromises KATNIP regulation and impairs primary cilia and Hedgehog signaling.

Mutations in human CILK1 (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent of the human CILK1 A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEF) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia and up-regulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. CILK1 A615T mutant protein was not increased to the same level as the wild type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single residue variant of CILK1 is compromised and this impairs the maintenance of primary cilia and Hedgehog signaling.

Framework for exploring the sensory repertoire of the human gut microbiota.

Bacteria sense changes in their environment and transduce signals to adjust their cellular functions accordingly. For this purpose, bacteria employ various sensors feeding into multiple signal transduction pathways. Signal recognition by bacterial sensors is studied mainly in a few model organisms, but advances in genome sequencing and analysis offer new ways of exploring the sensory repertoire of many understudied organisms. The human gut is a natural target of this line of study: it is a nutrient-rich and dynamic environment and is home to thousands of bacterial species whose activities impact human health. Many gut commensals are also poorly studied compared to model organisms and are mainly known through their genome sequences. To begin exploring the signals human gut commensals sense and respond to, we have designed a framework that enables the identification of sensory domains, prediction of signals that they recognize, and experimental verification of these predictions. We validate this framework's functionality by systematically identifying amino acid sensors in selected bacterial genomes and metagenomes, characterizing their amino acid binding properties, and demonstrating their signal transduction potential.IMPORTANCESignal transduction is a central process governing how bacteria sense and respond to their environment. The human gut is a complex environment with many living organisms and fluctuating streams of nutrients. One gut inhabitant, Escherichia coli, is a model organism for studying signal transduction. However, E. coli is not representative of most gut microbes, and signaling pathways in the thousands of other organisms comprising the human gut microbiota remain poorly understood. This work provides a foundation for how to explore signals recognized by these organisms.

Enhancing the Solubility, Stability, and Bioavailability of Retinol Acetate through Mechanochemistry.

This study utilizes mechanochemistry to prepare retinol acetate (RA) solid dispersion (RA-sodium starch octenyl succinate (SSOS)), resulting in improved solubility, stability, and bioavailability compared with raw RA and commercial RA microcapsules. RA, poloxamer 188, SSOS, and milling beads (8 mm) were mixed in a ratio of 2:1:8:220 (w/w) and ball-milled at 100 rpm for 3 h. RA-SSOS exhibited a solubility of 1020.35 µL/mL and a 98.09% retention rate after aging at 30 °C. Rats fed with RA-SSOS showed an ∼30% increase in organ RA content. Characterization analysis attributed the solubility and stabilization of RA-SSOS to hydrogen bonding between RA and SSOS, along with an amorphous state. RA-SSOS offers significant advantages for the pharmaceutical and food industries, leveraging mechanochemistry to enhance solid dispersions for hydrophobic compounds and optimize drug delivery.

Peripheral 5-HT Mediates Gonadotropin-Inhibitory Hormone-Induced Feeding Behavior and Energy Metabolism Disorder in Chickens via the 5-HT2C Receptor.

INTRODUCTION: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. METHODS: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. RESULTS: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. DISCUSSION: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders.

Internal water circulation mediated synergistic co-hydrolysis of PET/cotton textile blends in gamma-valerolactone.

Recycling strategies for mixed plastics and textile blends currently aim for recycling only one of the components. Here, we demonstrate a water coupling strategy to co-hydrolyze polyester/cotton textile blends into polymer monomers and platform chemicals in gamma-valerolactone. The blends display a proclivity for achieving an augmented 5-hydroxymethylfurfural yield relative to the degradation of cotton alone. Controlled experiments and preliminary mechanistic studies underscore that the primary driver behind this heightened conversion rate lies in the internal water circulation. The swelling and dissolving effect of gamma-valerolactone on polyester enables a fast hydrolysis of polyester at much lower concentration of acid than the one in the traditional hydrolysis methods, effectively mitigating the excessive degradation of cotton-derived product and undesirable product formation. In addition, the system is also applicable to different kinds of blends and PET mixed plastics. This strategy develops an attractive path for managing end-of-life textiles in a sustainable and efficient way.

Association between elevated preoperative red cell distribution width and mortality after brain tumor craniotomy.

BACKGROUND: Red cell distribution width (RDW) has been recognized as a potential inflammatory biomarker, with elevated levels associated with adverse outcomes in various diseases. However, its role in predicting outcomes after brain tumor craniotomy remains unclear. We aimed to assess whether preoperative RDW influences mortality and postoperative complications in patients undergoing brain tumor craniotomy. METHODS: This retrospective cohort study analyzed serum RDW levels in patients undergoing brain tumor craniotomy at West China Hospital. RDW was evaluated in two forms: RDW-CV and RDW-SD, and was categorized into four quartiles for analysis by using logistic regression and multivariate analysis to adjust for confounding. RESULTS: The study encompassed 10,978 patients undergoing brain tumor craniotomy. our analysis revealed no significant difference in 30-day mortality across various RDW-CV levels. However, we observed a dose-response relationship with preoperative RDW-CV levels in assessing long-term mortality risks. Specifically, patients with RDW-CV levels of 12.6-13.2% (HR 1.04, 95% CI 1.01-1.18), 13.2-13.9% (HR 1.12, 95% CI 1.04-1.26), and > 13.9% (HR 1.34, 95% CI 1.18-1.51) exhibited a significantly higher hazard of long-term mortality compared to those with RDW-CV < 12.6%. When preoperative RDW-CV was analyzed as a continuous variable, for each 10% increase in RDW-CV, the adjusted OR of long-term mortality was 1.09 (95% CI 1.05-1.13). we also observed significant associations between preoperative higher RDW-CV levels and certain postoperative complications including acute kidney injury (OR 1.46, 95% CI: 1.10-1.94), pneumonia infection (OR 1.19 95% CI: 1.05-1.36), myocardial infarction (OR 1.32, 95% CI: 1.05-1.66), readmission (OR 1.15, 95% CI: 1.01-1.30), and a prolonged length of hospital stay (OR 1.11, 95% CI: 1.02-1.21). For RDW-SD levels, there was no significant correlation for short-term mortality, long-term mortality, and postoperative complications. CONCLUSIONS: Our study showed elevated preoperative RDW-CV is significantly associated with increased long-term mortality and multiple postoperative complications, but no such association is observed with RDW-SD. These findings show the prognostic importance of RDW-CV, reinforcing its potential as a valuable tool for risk stratification in the preoperative evaluation of brain tumor craniotomy patients.

Tunable optical spatial differential operation via photonic spin Hall effect in a Weyl semimetal.

Optical differential operation is the basic principle of optical image edge detection, which has the advantages of high efficiency, simple structure and markerless compared with the traditional digital image processing methods. In this paper, we propose an optical differential operation with high contrast based on the photonic spin Hall effect in a Weyl semimetal, which enables to switch between one- and two-dimensional edge detection. Due to the unique optical and electrical properties of the Weyl semimetal, a transport model for the differential operation is established, which is closely related to the beam shifts. By tuning the incidence conditions, we effectively manipulate the in-plane and transverse shifts to switch differential operations between one and two dimensions. The contrast of the differential operation is further regulated by changing the physical parameters of the Weyl semimetal, and can be improved by two orders of magnitude compared to the conventional differentiator. This study provides new possibilities in edge detection and image processing owing to the advantages of switchable dimension and high contrast.

Reversibly Sticking Metals and Graphite to Hydrogels and Tissues.

We have discovered that hard, electrical conductors (e.g., metals or graphite) can be adhered to soft, aqueous materials (e.g., hydrogels, fruit, or animal tissue) without the use of an adhesive. The adhesion is induced by a low DC electric field. As an example, when 5 V DC is applied to graphite slabs spanning a tall cylindrical gel of acrylamide (AAm), a strong adhesion develops between the anode (+) and the gel in about 3 min. This adhesion endures after the field is removed, and we term it as hard-soft electroadhesion or EA[HS]. Depending on the material, adhesion occurs at the anode (+), cathode (-), or both electrodes. In many cases, EA[HS] can be reversed by reapplying the field with reversed polarity. Adhesion via EA[HS] to AAm gels follows the electrochemical series: e.g., it occurs with copper, lead, and tin but not nickel, iron, or zinc. We show that EA[HS] arises via electrochemical reactions that generate chemical bonds between the electrode and the polymers in the gel. EA[HS] can create new hybrid materials, thus enabling applications in robotics, energy storage, and biomedical implants. Interestingly, EA[HS] can even be achieved underwater, where typical adhesives cannot be used.

Enhancing the electric charge output in LiNbO3-based piezoelectric pressure sensors.

Lithium niobate (LiNbO3) single crystals are a kind of ferroelectric material with a high piezoelectric coefficient and Curie temperature, which is suitable for the preparation of piezoelectric pressure sensors. However, there is little research reporting on the use of LiNbO3 single crystals to prepare piezoelectric pressure sensors. Therefore, in this paper, LiNbO3 was used to prepare piezoelectric pressure sensors to study the feasibility of using LiNbO3 single crystals as a sensitive material for piezoelectric pressure sensors. In addition, chemical mechanical polishing (CMP) technology was used to prepare LiNbO3 crystals with different thicknesses to study the influence of these LiNbO3 crystals on the electric charge output of the sensors. The results showed that the sensitivity of a 300 µm sample (0.218 mV kPa-1) was about 1.23 times that of a 500 µm sample (0.160 mV kPa-1). Low-temperature polymer heterogeneous integration and oxygen plasma activation technologies were used to realize the heterogeneous integration of LiNbO3 and silicon to prepare piezoelectric pressure sensors, which could significantly improve the sensitivity of the sensor by approximately 16.06 times (2.569 mV kPa-1) that of the original sample (0.160 mV kPa-1) due to an appropriate residual stress that did not shatter LiNbO3 or silicon, thus providing a possible method for integrating piezoelectric pressure sensors and integrated circuits.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Peripheral inflammatory biomarkers as predictive tools for HyperCKemia risk assessment post-seizures.

BACKGROUND: This study evaluates the potential of inflammatory biomarkers, especially the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), for early detection of hyperCKemia after seizures. Addressing the challenge of delayed hyperCKemia diagnosis, which can escalate to rhabdomyolysis, this research emphasizes the use of these accessible biomarkers. METHODS: Conducted retrospectively, data from October 1, 2022, and October 1, 2023, were extracted from electronic medical records. Following univariate analysis (P-value < 0.05 for selection), Spearman's rank correlation and binary logistics regression were employed to examine the relationship between hyperCKemia and various clinical variables. Receiver operating characteristic curves (ROCs) defined the cut-off values for seizure-related hyperCKemia. RESULTS: Among 98 seizure patients, 31 (31.63 %) developed hyperCKemia. Notable differences in leukocytes, neutrophils, CRP, and NLR levels were observed between hyperCKemia and normal CK groups (P < 0.05). Leukocytes, NLR, and CRP correlated with hyperCKemia, exhibiting odds ratios of 1.24 (95 % CI: 1.11-1.39, P < 0.001), 1.03 (95 % CI: 1.01-1.05, P = 0.001), and 1.22 (95 % CI: 1.09-1.35, P = 0.017). The optimal cut-off values were established as 9.78 × 10^9/L for leukocytes, 32.40 mg/L for CRP, and 7.35 for NLR. CONCLUSION: Elevated levels of leukocytes, CRP, and NLR post-seizure are strong indicators of hyperCKemia risk, with significant implications for enhancing clinical decision-making and patient care strategies.

Expression of endogenous epitope-tagged GPR4 in the mouse brain.

GPR4 is a proton-sensing G protein-coupled receptor implicated in many peripheral and central physiological processes. GPR4 expression has previously been assessed only via detection of the cognate transcript or indirectly, by use of fluorescent reporters. In this work, CRISPR/Cas9 knock-in technology was used to encode a hemagglutinin (HA) epitope tag within the endogenous locus of Gpr4 and visualize GPR4-HA in the mouse central nervous system using a specific, well characterized HA antibody; GPR4 expression was further verified by complementary Gpr4 mRNA detection. HA immunoreactivity was found in a limited set of brain regions, including in the retrotrapezoid nucleus (RTN), serotonergic raphe nuclei, medial habenula, lateral septum, and several thalamic nuclei. GPR4 expression was not restricted to cells of a specific neurochemical identity as it was observed in excitatory, inhibitory, and aminergic neuronal cell groups. HA immunoreactivity was not detected in brain vascular endothelium, despite clear expression of Gpr4 mRNA in endothelial cells. In the RTN, GPR4 expression was detected at the soma and in proximal dendrites along blood vessels and the ventral surface of the brainstem; HA immunoreactivity was not detected in RTN projections to two known target regions. This localization of GPR4 protein in mouse brain neurons corroborates putative sites of expression where its function has been previously implicated (e.g., CO2-regulated breathing by RTN), and provides a guide for where GPR4 could contribute to other CO2/H+ modulated brain functions. Finally, GPR4-HA animals provide a useful reagent for further study of GPR4 in other physiological processes outside of the brain.Significance Statement GPR4 is a proton-sensing G-protein coupled receptor whose expression is necessary for a number of diverse physiological processes including acid-base sensing in the kidney, immune function, and cancer progression. In the brain, GPR4 has been implicated in the hypercapnic ventilatory response mediated by brainstem neurons. While knockout studies in animals have clearly demonstrated its necessity for normal physiology, descriptions of GPR4 expression have been limited due to a lack of specific antibodies for use in mouse models. In this paper, we implemented a CRISPR/Cas9 knock-in approach to incorporate the coding sequence for a small epitope tag into the locus of GPR4. Using these mice, we were able to describe GPR4 protein expression directly for the first time.

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma.

Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form under pathological conditions. However, the predictive value of TLS in clear cell renal cell carcinoma (ccRCC) for immunotherapies remains unclear. We comprehensively assessed the implications for prognosis and immunological responses of the TLS spatial and maturation heterogeneity in 655 ccRCC patients. A higher proportion of early-TLS was found in peritumoral TLS, while intratumoral TLS mainly comprised secondary follicle-like TLS (SFL-TLS), indicating markedly better survival. Notably, presence of TLS, especially intratumoral TLS and SFL-TLS, significantly correlated with better survival and objective reflection rate for ccRCC patients receiving anti-Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand-1 (PD-L1) immunotherapies. In peritumoral TLS cluster, primary follicle-like TLS, the proportion of tumor-associated macrophages, and Treg infiltration in the peritumoral regions increased prominently, suggesting an immunosuppressive tumor microenvironment. Interestingly, spatial transcriptome annotation and multispectral fluorescence showed that an abundance of mature plasma cells within mature TLS has the capacity to produce IgA and IgG, which demonstrate significantly higher objective response rates and a superior prognosis for ccRCC patients subjected to immunotherapy. In conclusion, this study revealed the implications of TLS spatial and maturation heterogeneity on the immunological status and clinical responses, allowing the improvement of precise immunotherapies of ccRCC.

Efficacy and Safety of Once-Weekly Insulin Regimes on Glycemic Control for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

BACKGROUND: Randomized controlled trials have found that once-weekly insulin resulted in greater glycemic control compared to once-daily insulin in patients with type 2 diabetes. However, no direct comparisons have been made between different types of once-weekly insulin thus far. This systematic review and network meta-analysis aimed to evaluate the effect of the two most advanced once-weekly insulin analogues, namely insulin icodec and insulin Fc, in patients with type 2 diabetes. METHODS: We conducted a thorough search in the databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials. The search included articles published from the beginning to October 10, 2023, with no language limitations. Our aim was to conduct a systematic review of randomized controlled trials that investigated the effectiveness and safety of once-weekly insulin in individuals with type 2 diabetes. Our primary outcome was to evaluate excellent glycemic control, defined as patients achieving glycated hemoglobin levels below 7%. RESULTS: We identified a total of 7 trials involving 2829 patients. The results showed that once-weekly insulin icodec is more effective than once-weekly insulin Fc (RR 1.59 [95% CI 1.08-2.38]), once-daily degludec (RR 1.43 [95% CI 1.14-1.83]), and once-daily glargine (RR 1.15 [95% CI 1.00-1.41]). Moreover, the incidence of severe hypoglycemia was lower with once-weekly insulin icodec compared to once-daily degludec (RR 0.00016 [95% CI 0 to 0.41]). However, no significant difference in the incidence of severe hypoglycemia was observed between once-weekly insulin icodec and once-daily glargine (RR 0.39 [95% CI 0.03 to 4.83]). CONCLUSIONS: In patients with type 2 diabetes, once-weekly insulin icodec achieved superior glycemic control compared to once-weekly insulin Fc, with no significant difference in the occurrence of hypoglycemia. The ranking probability results have shown that one weekly icodec seems to be the preferred option in patients with type 2 diabetes. TRIAL REGISTRATION: PROSPERO Identifier: CRD42023470894.

Single-cell RNA-seq analysis decodes the kidney microenvironment induced by polystyrene microplastics in mice receiving a high-fat diet.

In recent years, the environmental health issue of microplastics has aroused an increasingly significant concern. Some studies suggested that exposure to polystyrene microplastics (PS-MPs) may lead to renal inflammation and oxidative stress in animals. However, little is known about the essential effects of PS-MPs with high-fat diet (HFD) on renal development and microenvironment. In this study, we provided the single-cell transcriptomic landscape of the kidney microenvironment induced by PS-MPs and HFD in mouse models by unbiased single-cell RNA sequencing (scRNA-seq). The kidney injury cell atlases in mice were evaluated after continued PS-MPs exposure, or HFD treated for 35 days. Results showed that PS-MPs plus HFD treatment aggravated the kidney injury and profibrotic microenvironment, reshaping mouse kidney cellular components. First, we found that PS-MPs plus HFD treatment acted on extracellular matrix organization of renal epithelial cells, specifically the proximal and distal convoluted tubule cells, to inhibit renal development and induce ROS-driven carcinogenesis. Second, PS-MPs plus HFD treatment induced activated PI3K-Akt, MAPK, and IL-17 signaling pathways in endothelial cells. Besides, PS-MPs plus HFD treatment markedly increased the proportions of CD8+ effector T cells and proliferating T cells. Notably, mononuclear phagocytes exhibited substantial remodeling and enriched in oxidative phosphorylation and chemical carcinogenesis pathways after PS-MPs plus HFD treatment, typified by alterations tissue-resident M2-like PF4+ macrophages. Multispectral immunofluorescence and immunohistochemistry identified PF4+ macrophages in clear cell renal cell carcinoma (ccRCC) and adjacent normal tissues, indicating that activate PF4+ macrophages might regulate the profibrotic and pro-tumorigenic microenvironment after renal injury. In conclusion, this study first systematically revealed molecular variation of renal cells and immune cells in mice kidney microenvironment induced by PS-MPs and HFD with the scRNA-seq approach, which provided a molecular basis for decoding the effects of PS-MPs on genitourinary injury and understanding their potential profibrotic and carcinogenesis in mammals.

The Effects of Zinc Oxide Nanoparticles on Antioxidation, Inflammation, Tight Junction Integrity, and Apoptosis in Heat-Stressed Bovine Intestinal Epithelial Cells In Vitro.

Zinc oxide nanoparticles (nano-ZnO) have diverse applications in numerous biomedical processes. The present study explored the effects of these nanoparticles on antioxidation, inflammation, tight junction integrity, and apoptosis in heat-stressed bovine intestinal epithelial cells (BIECs). Primary BIECs that were isolated and cultured from calves either were subjected to heat stress alone (42°C for 6 h) or were simultaneously heat-stressed and treated with nano-ZnO (0.8 µg/mL). Cell viability, apoptosis, and expression of genes involved in antioxidation (Nrf2, HO-1, SOD1, and GCLM), inflammation-related genes (TLR4, NF-κB, TNF-α, IL-6, IL-8, and IL-10), intestinal barrier genes (Claudin, Occludin, and ZO-1), and apoptosis-related genes (Cyt-c, Caspase-3, and Caspase-9) were assessed to evaluate the effect of nano-ZnO on heat-stressed BIECs. The nanoparticles significantly increased cell viability and decreased the rate of apoptosis of BIECs induced by heat stress. In addition, nano-ZnO promoted the expression of antioxidant-related genes HO-1 and GCLM and anti-inflammatory cytokine gene IL-10, and inhibited the pro-inflammatory cytokine-related genes IL-6 and IL-8. The nanoparticles also enhanced expression of the Claudin and ZO-1 genes, and decreased expression of the apoptosis-related genes Cyt-c and Caspase-3. These results reveal that nano-ZnO improve the antioxidant and immune capacity of BIECs and mitigate apoptosis of intestinal epithelial cells induced by heat stress. Thus, nano-ZnO have potential for detrimental the adverse effects of heat stress in dairy cows.