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Coming from the commognitive standpoint, we consider proof-based mathematics as a distinct discourse, the transition to which requires special rules for endorsement and rejection of mathematical statements. In this study, we investigate newcomers' learning of these rules when being taught them explicitly. Our data come from academically motivated high-school students who took a special course in undergraduate mathematics. The course teacher dedicated three academic hours to introducing and explaining selected rules of proof to support students' shift to the new discourse. The homework assignment consisted of typical proof-requiring problems and a scriptwriting task, asking students to compose a dialogue between fictional characters about a proof-related mistake of their choice. We analyzed the differences and similarities between the rules discussed in the classroom and those that students addressed and implemented in their proofs. The analysis showed that while students' solutions to proof-requiring problems required rule implementation, fictitious dialogues opened the space for rule formulation and substantiation. In many cases, the students discussed the rules presented in the classroom, extending, elaborating, and specifying the teacher's formulations. Furthermore, while the students' proofs were mainly consistent with the teacher's expectations, some of their rule formulations were more radical and overgeneralized than expected. These findings suggest that newcomers' communication about the rules of proof may lag behind their capability to implement those rules to prove mathematical statements.

Abstract This study aimed to compare the clinical efficacy and investigate patients’ preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p

Dopamine-modified hyaluronic acid (DA-HA) has been initially developed as an efficient coating and adhesion material for industrial uses. However, the biological activity and safety of DA-HA in the brain have not been explored yet. Here, we report a series of evidence that DA-HA exhibits similar functionality as dopamine (DA), but with much lower toxicity arising from autoxidation. DA-HA shows very little autoxidation even after 48-h incubation. This is profoundly different from DA and its derivatives including l-DOPA, which all induce severe neuronal death after pre-autoxidation, indicating that autoxidation is the cause of neuronal death. Furthermore, in vivo injection of DA-HA induces significantly lower toxicity compared to 6-OHDA, a well-known oxidized and toxic form of DA, and alleviates the apomorphine-induced rotational behavior in the 6-OHDA animal model of Parkinson's disease. Our study proposes that DA-HA with DA-like functionalities and minimal toxicity has a great potential to treat DA-related disease.

Organoids significantly advanced our comprehension of organ development, function, and disease modeling. This Perspective underscores the potential of heart–kidney-connected organoids in understanding the intricate relationship between these vital organs, notably the cardiorenal syndrome, where dysfunction in one organ can negatively impact the other. Conventional models fall short in replicating this complexity, necessitating an integrated approach. By co-culturing heart and kidney organoids, combined with microfluidic and 3D bioprinting technologies, a more accurate representation of in vivo conditions can be achieved. Such interconnected systems could revolutionize our grasp of multi-organ diseases, drive drug discovery by evaluating therapeutic agents on both organs simultaneously, and reduce the need for animal models. In essence, heart–kidney-connected organoids present a promising avenue to delve deeper into the pathophysiology underlying cardiorenal disorders, bridging existing knowledge gaps, and advancing biomedical research.

Abstract Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.

Abstract Background In case of focal neuropathy, the muscle fibers innervated by the corresponding nerves are replaced with fat or fibrous tissue due to denervation, which results in increased echo intensity (EI) on ultrasonography. EI analysis can be conducted quantitatively using gray scale analysis. Mean value of pixel brightness of muscle image defined as EI. However, the accuracy achieved by using this parameter alone to differentiate between normal and abnormal muscles is limited. Recently, attempts have been made to increase the accuracy using artificial intelligence (AI) in the analysis of muscle ultrasound images. CTS is the most common disease among focal neuropathy. In this study, we aimed to verify the utility of AI assisted quantitative analysis of muscle ultrasound in CTS. Methods This is retrospective study that used data from adult who underwent ultrasonographic examination of hand muscles. The patient with CTS confirmed by electromyography and subjects without CTS were included. Ultrasound images of the unaffected hands of patients or subjects without CTS were used as controls. Ultrasonography was performed by one physician in same sonographic settings. Both conventional quantitative grayscale analysis and machine learning (ML) analysis were performed for comparison. Results A total of 47 hands with CTS and 27 control hands were analyzed. On conventional quantitative analysis, mean EI ratio (i.e. mean thenar EI/mean hypothenar EI ratio) were significantly higher in the patient group than in the control group, and the AUC was 0.76 in ROC analysis. In the analysis using machine learning, the AUC was the highest for the linear support vector classifier (AUC = 0.86). When recursive feature elimination was applied to the classifier, the AUC value improved to 0.89. Conclusion This study showed a significant increase in diagnostic accuracy when AI was used for quantitative analysis of muscle ultrasonography. If an analysis protocol using machine learning can be established and mounted on an ultrasound machine, a noninvasive and non-time-consuming muscle ultrasound examination can be conducted as an ancillary tool for diagnosis.

AbstractCassia tora Linn. is a medicinal herb that has traditionally been used to prevent diseases. The study investigated the changes in bioactive compounds of Cassia tora seeds during 3-days of germination. The seeds were thoroughly cleaned, soaked in deionized water at 20 °C for 2 h, and germinated at 25 °C and 90% relative humidity in a seed germinator. Germinating C. tora seeds were picked up at 24 h intermissions over 3-day germination duration. The germinating C. tora was freeze-dried and pulverized through a 1 mm mesh screen. During the germination process, the crude ash, crude fat, and crude protein content of C. tora seeds increased slightly. The main carotenoid compounds identified in this study were lutein and β-carotenes, and the total carotenoid content increased up to 4.35 µg/g after 72-hours of germination, which was 1.73-times higher compared to that in raw C. tora seeds. The anthocyanin and vitamin C content also increased during the germination period, being 1.44-times and 1.72-times, respectively, higher after 72-hours of germination than that in the raw C. tora seeds. In addition, phenolics and flavonoids in C. tora seeds had a tendency to increase after germination, subsequently increasing in vitro antioxidant activities (ABTS and DPPH-radical scavenging activities). Proper germination of C. tora might be a convenient and efficient method to increase antioxidant bioactive compounds in our diet to exploit the related health benefits.

PurposeThe purpose of this study was to access the ability of the natural PPAR agonist, eicosapentaenoic acid (EPA), to activate PPAR gamma (γ) signaling leading to meibocyte differentiation in human meibomian gland epithelial cell (hMGEC).MethodsHMGEC were exposed to EPA, alone and in combination with the specific PPARγ antagonist, T0070907, to selectively block PPARγ signaling. Expression of PPARγ response genes were evaluated by qPCR. Effect on cell cycle was evaluated using Ki-67 labelling and western blots. During differentiation, autophagy was monitored using the Autophagy Tandem Sensor (ATS) and LysoTracker. Lipid accumulation was characterized by Stimulated Raman Scattering microscopy (SRS) and neutral lipid staining in combination with ER-Tracker, LysoTracker, and ATS. Autophagy was also investigated using western blotting. Seahorse XF analysis was performed to monitor mitochondrial function.ResultsEPA specifically upregulated expression of genes related to lipid synthesis and induced cell cycle exit through reduced cyclin D1 expression and increased p21 and p27 expression. EPA also induced accumulation of lipid droplets in a time and dose dependent manner (P

Purpose:We have shown that nonlinear optical corneal crosslinking (NLO CXL) and stiffening can be achieved in ex vivo rabbit corneas using an 80-MHz, 760-nm femtosecond (FS) laser, however the required power was beyond the American National Standard Institute limit. The purpose of this study was to test the efficacy of amplified FS pulses to perform CXL to reduce power by increasing pulse energy. Methods:A variable numerical aperture laser scanning delivery system was coupled to a 1030-nm laser with a noncollinear optical parametric amplifier to generate 760 nm, 50 to 150 kHz amplified FS pulses with 79.5-μm axial and 2.9-μm lateral two-photon focal volume. Ex vivo rabbit corneas received NLO CXL, and effectiveness was assessed by measuring collagen autofluorescence (CAF) and mechanical stiffening. NLO CXL was also performed in 14 live rabbits, and changes in corneal topography were measured using an Orbscan. Results:Amplified pulses (0.3 μJ) generated significant CAF that increased logarithmically with decreasing scan speed; achieving equivalent CAF to UVA CXL at 15.5 mm/s. Indentation testing detected a 62% increase in stiffness compared to control, and corneal topography measurements revealed a significant decrease of 1.0 ± 0.8 diopter by 1 month (P < 0.05). Conclusions:These results show that NLO CXL using amplified pulses can produce corneal collagen CXL comparable to UVA CXL. Translational Relevance:NLO CXL using amplified pulses can produce corneal CXL comparable to UVA CXL, suggesting a potential clinical application in which NLO CXL can be used to perform personalized crosslinking for treatment of refractive errors and keratoconus.

PurposePPARγ plays a critical role in the maturation of immortalized human meibomian gland epithelial cells (hMGEC). To further understand the molecular changes associated with meibocyte differentiation, we analyzed transcriptome profiles from hMGEC after PPARγ activation.MethodsThree sets of cultivated hMGEC with or without exposure to PPARγ agonist, rosiglitazone were used for RNA-seq analysis. RNA was isolated and processed to generate 6 libraries. The libraries were then sequenced and mapped to the human reference genome, and the expression results were gathered as reads per length of transcript in kilobases per million mapped reads (RPKM) values. Differential gene expression analyses were performed using DESeq2 and NOISeq. Gene ontology enrichment analysis (GOEA) was performed on gene sets that were upregulated or downregulated after rosiglitazone treatment. Five genes were selected for validation and differential expression was confirmed using quantitative PCR. The Differential expression of CK5 was evaluated using Western blotting.ResultsExpression data indicated that about 58,000 genes are expressed in hMGEC. DESeq2 and NOISeq indicated that 296 and 3436 genes were upregulated and 258 and 3592 genes were down regulated after rosiglitazone treatment, respectively. Of genes showing significant differences > 2 fold, GOEA indicated that cellular and metabolic processes were highly represented. Expression of ANGPTL4, PLIN2, SQSTM1, and DDIT3 were significantly upregulated and HHIP was downregulated by rosiglitazone. CK5 was downregulated by rosiglitazone.ConclusionsThe RNA-seq data suggested that PPARγ activation induced alterations in cell differentiation and metabolic process and affected multiple signaling pathways such as PPAR, autophagy, WNT, and Hedgehog.