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Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora. Glaucoma is a neurodegenerative disease of which the etiology is still unclear. Here the authors show that elevation of intraocular pressure induces T cell infiltration in the eyes. Furthermore, they show that T cell cross-reactivity between endogenous and commensal antigens contributes to disease onset in mice.

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies. Most people have likely experienced the discomfort of an eyelash falling onto the surface of their eye. Or that gritty sensation when dust blows into the eye and irritates the surface. These sensations are warnings from sensory nerves in the cornea, the transparent tissue that covers the iris and pupil. Corneal nerves help regulate blinking, and control production of the tear fluid that protects and lubricates the eye. But if the cornea suffers damage or infection, it can become inflamed. Long-lasting inflammation can damage the corneal nerves, leading to pain and vision loss. If scientists can identify how this happens, they may ultimately be able to prevent it. To this end, Royer et al. have used mice to study three causes of hard-to-treat corneal inflammation. The first is infection with herpes simplex virus (HSV-1), which also causes cold sores. The second is eye allergy, where the immune system overreacts to substances like pollen or pet dander. And the third is graft-versus-host disease (GVHD), an immune disorder that can affect people who receive a bone marrow transplant. Royer et al. showed that HSV-1 infection and GVHD – but not allergies – made the mouse cornea less sensitive to touch. Consistent with this, microscopy revealed damage to corneal nerves in the mice with HSV-1 infection and those with GVHD. Further experiments showed that immune cells called CD4 T cells and a protein called complement C3 were contributing to this nerve damage. Treating the mice with an experimental drug derived from cobra venom protected the cornea from the harmful effects of inflammation. It did so by blocking activation of complement C3 at the eye surface. Identifying factors such as complement C3 that are responsible for corneal nerve damage is an important first step in helping patients with inflammatory eye diseases. Many drugs that target the complement pathway are currently under development. Some of these drugs could potentially be adapted for delivery as eye drops. But first, experiments must test whether complement also contributes to corneal nerve damage in humans. If it does, work can then begin on testing these drugs for safety and efficacy in patients.

The current studies have critical limitations such as lack of real-world deployment, biases in Electronic Health Records (EHR)-based models, and computational ineffectiveness. This paper proposes an advanced ML framework incorporating transformer-based deep learning architectures, fairness-aware training, privacy-preserving federated learning in order to focus on those challenges. In contrast to existing models which target specific disease classes, the proposed system generalises across chronic and acute conditions, while ensuring scalability in low-resource settings. In addition, the study enhances prediction reliability with the use of real-time knowledge graphs, AI-powered decision support systems, and bias-mitigation strategies. This work uses real-world hospital data to validate the model, creating a practical roadmap for the adoption of AI in healthcare effectively connecting the dots between theoretical progress and real-world clinical practice. The results enhance early detection of diseases, tailored treatment plans and the reduction of health inequalities establishing predictive analytics driven by AI as one of the tools that will change the face of modern medicine.

Steady state dendritic cells (DC) found in non-lymphoid tissue sites under normal physiologic conditions play a pivotal role in triggering T cell responses upon immune provocation. CD11b+ and CD103+ DC have received considerable attention in this regard. However, still unknown is whether such CD11b+ and CD103+ DC even exist in the ocular mucosa, and if so, what functions they have in shaping immune responses. We herein identified in the ocular mucosa of normal wild-type (WT) and Flt3-/- mice the presence of a CD11b+ DC (i.e., CD11c+ MHCII+ CD11b+ CD103- F4/80+ Sirp-a+). CD103+ DC (i.e. CD11c+ MHCII+ CD11b low CD103+ CD8a+ DEC205+ Langerin+) were also present in WT, but not in Flt3-/- mice. These CD103+ DC expressed high levels of Id2 and Flt3 mRNA; whereas CD11b+ DC expressed high Irf4, Csfr, and Cx3cr1 mRNA. Additionally, the functions of these DC differed in response to allergic immune provocation. This was assessed utilizing a previously validated model, which includes transferring specific populations of exogenous DC into the ocular mucosa of ovalbumin (OVA)/alum-primed mice. Interestingly, in such mice, topical OVA instillation following engraftment of exogenous CD11b+ DC led to dominant allergic T cell responses and clinical signs of ocular allergy relative to those engrafted with CD103+ DC. Thus, although CD11b+ and CD103+ DC are both present in the normal ocular mucosa, the CD11b+ DC subset plays a dominant role in a mouse model of ocular allergy.

Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.

PurposeThe purpose of this study is to predict the intention to continue online learning post the coronavirus disease 2019 (COVID-19) pandemic among students in the two largest universities of higher learning in Botswana. Furthermore, the purposes of this study are to elucidate the nexus between performance expectancy and continuance intention to establish the effects of efforts expectancy on continuance intention to investigate the relationship between social influence and continuance intention to determine the relationship between facilitating conditions and continuance intention and to examine the relationship between satisfaction and continuance intention using the extended unified theory of acceptance and usage technology (UTAUT) model postulated by Venkatesh et al. (2003).Design/methodology/approachThe study is based on the descriptive research design, using a structured questionnaire to collect quantitative data from 509 undergraduate and postgraduate students at Botswana's two major Universities using convenience sampling strategy. An online survey was used to gather primary data due to the COVID-19 pandemic. The study employed correlation and regression analysis in testing the five hypothesized relationships.FindingsUsing the extended theory of UTAUT as a theoretical lens, the study found that: performance expectancy, social influence and satisfaction predict continuance intention of online learning services. These factors have shown to be good predictors of intention in previous research. Expectancy effort had no influence on intention.Research limitations/implicationsThe current study covered on only university students from two tertiary institutions; therefore, results cannot safely be generalized to the student population in the country. Therefore, future research should consider enlisting more universities to be more representative, focusing on lecturers, which is an important group in fostering online teaching that could have a spill-over effect on the students' continued online learning.Practical implicationsImplications for online technology selection: These findings suggest that although most universities temporarily adopted online teaching as an emergency solution, students appear to have felt that the outcomes delivered by the system improved their performance. This implies that academic institutions need to consider adjusting the curriculum to promote online learning in the future, whether there is pandemic or no pandemic. Implications for teaching and learning: First, the concept of social influence suggests that lecturers can make use of online chat discussion boards and rooms to foster student collaboration and a sense of community. Second, and finally online service providers should foster a close relationship with students to understand their expectations and extend the performance of their applications to satisfy their users.Originality/valueThis study contributes to literature on online learning during the COVID-19 pandemic period by including satisfaction and continuance intention to the original UTAUT model thus extending the practical value of the model. This study extends knowledge on the factors that determine continuance intention by incorporating satisfaction in addition to the four factors of the traditional UTAUT. The study provides evidence for the predominance of satisfaction over the four traditional factors in predicting intention to continue online learning among students.

The originally published version of this Article contained an error in Figure 4. The bar chart in panel f was inadvertently replaced with a duplicate of the bar chart in panel e. This error has now corrected in both the PDF and HTML versions of the Article.

Fruit and vegetable processing byproducts have a high concentration of biologically useful components and nutritional fibre, though they are frequently discarded as manufacturing waste. The purpose of this study was to improve the nutritional value of the Indian recipe papad, a low-moisture dish with a thin, crisp, wafer-like texture, by utilizing the beneficial properties of dehydrated carrot pomace powder (CPP), which is usually discarded as a food industry bio-waste. Carrot pomace powder was prepared and examined for nutritional and functional properties (10, 20, and 30%), and the developed samples were coded as P0 (control, 100% black gram flour), P1 (black gram flour: carrot pomace powder; 90:10), P2 (black gram flour: carrot pomace powder; 80:20), and P3 (black gram flour: carrot pomace powder; 70:30). The physical, sensory, and storage properties of the developed value-added papads were evaluated. Adding CPP to the flour mix increased the moisture, ash, and crude fiber content while decreasing the protein and carbohydrate content. Based on sensory evaluation, sample P1 was found to be the most acceptable by the sensory panel. The product's microbiological studies showed that, up to a 30-day storage period, the product was well within safe limits. Based on the water activity (at 36.7ºC/ 83% RH) and overall acceptability scores, triple-laminated aluminum bags were considered an appropriate packaging material for storing the value-added papads. This study has established the incorporation of CPP as a healthier alternative to produce an inexpensive, fiber-rich, value-added papads.  

Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p < 0.0001) with reference to EGFR-AS1 expression levels, consistent with larger TCGA HNSCC tumor dataset. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of intronic polyA sites spanning around exon 15a and 15b of EGFR facilitates skipping of exon 15b, thereby promoting the splicing of EGFR-A isoform. In addition, high level expression of PTBP1 and its binding site in EGFR and EGFR-AS1 enhances the expression of EGFR-A isoform (r = 0.7404, p < 0.0001) suggesting that EGFR-AS1 expression modulates the EGFR-A and D isoforms through alternative splicing. In addition, this polymorphism creates a binding site for miR-891b in EGFR-AS1 and may negatively regulate the EGFR-A. Collectively, our results suggested the presence of genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms.