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In this study, we investigate the upper- and lower-bound approximations of numerical eigenvalues derived by weak Galerkin spectral element methods on arbitrary convex quadrilateral meshes for the Laplace eigenvalue problem. Firstly, the Piola transformation is employed to construct the approximation space for weak gradients on each convex quadrilateral element, while a one-to-one mapping is used to establish the approximation space for weak functions. Subsequently, based on the weak Galerkin spectral element approximation space defined on convex quadrilateral meshes, a Galerkin approximation scheme is formulated, and its well-posedness is then analyzed. Furthermore, numerical experiments are performed on arbitrary convex quadrilateral meshes of the square and L-shaped domains to explore the upper- and lower-bound approximations of numerical eigenvalues. Numerical findings indicate that the presented method not only obtains optimal orders of convergence with respect to both the mesh size and the polynomial degree, but also provides upper- and lower-bound approximations for the reference eigenvalues by proper choices of polynomial degrees in approximation spaces and parameters of the approximation scheme in both h-version and p-version weak Galerkin spectral element methods. This study offers new perspectives and methodologies for the high-precision numerical solution of eigenvalue problems in elliptic equations.

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel V H H nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1 ) associated with high T-cell polyfunctionality. This study demonstrates the potential of V H H-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes. Glypican-1 (GPC1) expression is elevated in pancreatic cancer and has been exploited as a therapeutic target. Here the authors report the development of V H H nanobody-based CAR-T cells targeting GPC1, showing anti-tumor activity in pancreatic cancer preclinical models.

Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant’s growth and increases 13 C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite’s fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13 C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5′-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen. Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis. Here, Guo and Ji et al. show that multiple routes can flexibly supply R5P to enable Toxoplasma gondii growth.

Patients admitted to the intensive care unit (ICU) have a high risk of refeeding syndrome (RFS). Identifying RFS in its early stages is often challenging, making preventive interventions for high-risk patients difficult. The aim of this review is to identify risk factors for RFS in ICU patients receiving nutritional support. We systematically searched CNKI, Wanfang, VIP, PubMed, Cochrane, Embase, and Web of Science up to November 2024 for cohort/case-control studies assessing RFS risk factors in adults (≥ 18 years). Risk of bias was evaluated using Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I). Data were analyzed using RevMan 5.4. Eighteen articles were included, comprising 3360 cases. Baseline serum phosphate [weighted mean difference (WMD) = -0.10, 95% confidence interval (95% CI) (-0.19∼-0.01)], magnesium [WMD = -0.01, 95% CI (-0.04-0.02)], potassium [WMD = -0.02, 95% CI (-0.06-0.02)], albumin [WMD = -2.08, 95% CI (-3.81, -0.36)], prealbumin [(WMD = -15.37, 95% CI (-33.00-2.27)], daily protein intake [WMD = 0.23, 95% CI (0.17-0.28)], APACHE II score [WMD = 2.65, 95% CI (1.22-4.08)], NRS2002 score [WMD = 0.68, 95% CI (-0.41-1.77)], SOFA score [WMD = 1.87, 95% CI (1.50-2.25)], age [WMD = 8.67, 95% CI (7.14-10.19)], daily calorie intake [odds ratio (OR) = 0.35, 95% CI (0.25, 0.49)], feeding within 48 h of ICU admission [OR = 1.98, 95% CI (1.56, 2.51)], and a history of diabetes [OR = 3.84, 95% CI (1.17, 12.59)] are the risk factors for meta-analysis in this article. The ROBINS-I assessment showed moderate-to-severe bias (10 severe, 8 moderate). The meta-analysis identified serum levels of phosphorus and albumin; daily protein and calorie intake; APACHE II score; SOFA score; age; initiation of feeding within 48 h of ICU admission; and a history of diabetes as significant predictors of RFS development in critically ill patients. Serum levels of magnesium, potassium, and prealbumin and the NRS2002 score were not associated with RFS in these patients.

The success of mRNA vaccines during the COVID-19 pandemic has revealed a revolutionary platform for addressing neglected parasite zoonosis, which represent a continual and significant threat to world health, especially in resource-constrained settings. The current review consolidates recent progress in the development of mRNA-based treatments, vaccines, and diagnostic ways for these pathogens. We elucidate how customized delivery platforms, particularly lipid nanoparticles, augment the stability and immunogenicity of parasite-derived mRNA cargo by safeguarding it from degradation and promoting uptake by antigen-presenting cells. Our findings suggest that mRNA technology provides a particularly adaptable strategy to targeting complicated parasite life cycles and efficiently modulating host immune responses. However, important challenges, such as cold-chain logistics, scalability, clinical trial design for diverse populations, and managing public opinion, must be solved beforehand. Future initiatives must priorities the creation of thermostable formulations and effective community participation strategies. Finally, this review emphasizes that mRNA-based interventions represent a promising, albeit challenging, frontier in the fight against parasitic diseases, urging a collaborative cross-disciplinary effort to translate this potential into tangible health breakthroughs for the world’s most vulnerable populations. Graphical abstract

Background Cervical cancer remains a significant global health issue, with accurate differentiation between low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL) crucial for effective screening and management. Current methods, such as Pap smears and HPV testing, often fall short in sensitivity and specificity. Deep learning models hold the potential to enhance the accuracy of cervical cancer screening but require thorough evaluation to ascertain their practical utility. Methods This study compares the performance of two advanced deep learning models, SEResNet101 and SE-VGG19, in classifying cervical lesions using a dataset of 3,305 high-quality colposcopy images. We assessed the models based on their accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results The SEResNet101 model demonstrated superior performance over SE-VGG19 across all evaluated metrics. Specifically, SEResNet101 achieved a sensitivity of 95%, a specificity of 97%, and an AUC of 0.98, compared to 89% sensitivity, 93% specificity, and an AUC of 0.94 for SE-VGG19. These findings suggest that SEResNet101 could significantly reduce both over- and under-treatment rates by enhancing diagnostic precision. Conclusion Our results indicate that SEResNet101 offers a promising enhancement over existing screening methods, integrating advanced deep learning algorithms to significantly improve the precision of cervical lesion classification. This study advocates for the inclusion of SEResNet101 in clinical workflows to enhance cervical cancer screening protocols, thereby improving patient outcomes. Future work should focus on multicentric trials to validate these findings and facilitate widespread clinical adoption.

Dendrobium is one of the largest genera in Orchidaceae, comprising about 800–1500 species mainly distributed in tropical Asia, Australasia, and Australia. There are 74 species and two varieties of this genus in China. Because of their ornamental and commercial value, Dendrobium orchids have been studied at low taxonomic levels. However, structural changes and effective mutational hotspots of Dendrobium plastomes have rarely been documented. Here, 30 Dendrobium plastomes were compared, comprising 25 newly sequenced in this study and five previously published. Except for their differences in NDH genes, these plastomes shared identical gene content and order. Comparative analyses revealed that the variation in size of Dendroubium plastomes was associated with dramatically changed length of InDels. Furthermore, ten loci were identified as the top-ten mutational hotspots, whose sequence variability was almost unchanged with more than 10 plastomes sampled, suggesting that they may be powerful markers for Dendrobium species. In addition, primer pairs of 47 polymorphic microsatellites were developed. After assessing the mean BS values of all combinations derived from the top-ten hotspots, we recommend that the combination of five hotspots— trnT - trnL , rpl32 - trnL , clpP - psbB , trnL intron , and rps16 - trnQ —should be used in the phylogenetic and identification studies of Dendrobium .

Background Overweight and obese females demonstrate a significantly increased risk of anovulatory infertility. This study aims to investigate whether depression score could mediate the association between a body shape index (ABSI) and infertility, especially in overweight and obese population. Methods We included 5431 adult female Americans from the National Health and Nutrition Examination Survey (NHANES, 2013–2018) database. ABSI manifested the body shape using waist circumference, weight, and height. Infertility or fertility status was defined by interviewing female participants aged ≥ 18 through the reproductive health questionnaires. Depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) with total scores between 0 and 27. To investigate the association of infertility with ABSI and other individual components, survey-weighted multivariable logistic regression was performed. Mediation analysis of PHQ-9 score was conducted to disentangle the pathways that link ABSI to infertility among the NHANES participants. Results 596 (10.97%) females were categorized with having infertility among 5431 participants. Participants with infertility showed higher ABSI and PHQ-9 score, appearing greater population proportion with depression symptoms. In the multivariable logistic regression model, ABSI (adjusted odds ratio = 0.14, 95% CI: 0.04 to 0.50) and PHQ-9 (adjusted odds ratio = 1.04, 95% CI: 1.01 to 1.07) were positively associated with infertility. PHQ-9 score was estimated to mediate 0.2% ( P  = 0.03) of the link between ABSI and infertility in all individuals, but to mediate 13.5% ( P  < 0.01) of the ABSI-infertility association in overweight and obese adult females. Conclusion The association between ABSI and infertility seems to be mediated by depression symptoms scored by PHQ-9, especially in those adult females with overweigh and obesity. Future studies should be implemented to further explore this mediator in ABSI-infertility link.

5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown. This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through experiments. Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative 5-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-3, ATG13, ULK1, and TFEB). Furthermore, the PI3K/AKT/mTOR signaling pathway and mTORC1 signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC1 signaling pathway (mLST8, RHEB, and TSC2). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to 5-FU through the PI3K/AKT/mTOR signaling pathway. The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to 5-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for 5-FU-related chemotherapy administered to GC patients with elevated THADA expression.