CD26 is a leukocyte-activation antigen that is expressed on T lymphocytes and macrophages and possesses dipeptidyl peptidase IV (DPPIV) activity, whose natural substrates have not been identified yet. CXC chemokines, stromal cell-derived factor 1␣ (SDF-1␣) and 1␤ (SDF-1␤), sharing the receptor CXCR-4, are highly efficacious chemoattractants for resting lymphocytes and CD34 ؉ progenitor cells, and they efficiently block the CXCR-4-mediated entry into cells of T cell line tropic strains of HIV type 1 (HIV-1). Here we show that both the chemotactic and antiviral activities of these chemokines are abrogated by DPPIV-mediated specific removal of the N-terminal dipeptide, not only when the chemokines are produced in transformed mouse L cell line to express human CD26 but also when they were exposed to a human T cell line (H9) physiologically expressing CD26. Mutagenesis of SDF-1␣ confirmed the critical requirement of the N-terminal dipeptide for its chemotactic and antiviral activities. These data suggest that CD26-mediated cleavage of SDF-1␣ and SDF-1␤ likely occurs in human bodies and promotes HIV-1 replication and disease progression. They may also explain why memory function of CD4 ؉ cells is preferentially lost in HIV-1 infection. Furthermore, CD26 would modulate various other biological processes in which SDF-1␣ and SDF-1␤ are involved.

Background CC-Cruiser is an artificial intelligence (AI) platform developed for diagnosing childhood cataracts and providing risk stratification and treatment recommendations. The high accuracy of CC-Cruiser was previously validated using specific datasets. The objective of this study was to compare the diagnostic efficacy and treatment decision-making capacity between CC-Cruiser and ophthalmologists in real-world clinical settings. Methods This multicentre randomized controlled trial was performed in five ophthalmic clinics in different areas across China. Pediatric patients (aged ≤ 14 years) without a definitive diagnosis of cataracts or history of previous eye surgery were randomized (1:1) to receive a diagnosis and treatment recommendation from either CC-Cruiser or senior consultants (with over 5 years of clinical experience in pediatric ophthalmology). The experts who provided a gold standard diagnosis, and the investigators who performed slit-lamp photography and data analysis were blinded to the group assignments. The primary outcome was the diagnostic performance for childhood cataracts with reference to cataract experts' standards. The secondary outcomes included the evaluation of disease severity and treatment determination, the time required for the diagnosis, and patient satisfaction, which was determined by the mean rating. This trial is registered with ClinicalTrials.gov ( NCT03240848 ). Findings Between August 9, 2017 and May 25, 2018, 350 participants (700 eyes) were randomly assigned for diagnosis by CC-Cruiser (350 eyes) or senior consultants (350 eyes). The accuracies of cataract diagnosis and treatment determination were 87.4% and 70.8%, respectively, for CC-Cruiser, which were significantly lower than 99.1% and 96.7%, respectively, for senior consultants ( p < 0.001, OR = 0.06 [95% CI 0.02 to 0.19]; and p < 0.001, OR = 0.08 [95% CI 0.03 to 0.25], respectively). The mean time for receiving a diagnosis from CC-Cruiser was 2.79 min, which was significantly less than 8.53 min for senior consultants ( p < 0.001, mean difference 5.74 [95% CI 5.43 to 6.05]). The patients were satisfied with the overall medical service quality provided by CC-Cruiser, typically with its time-saving feature in cataract diagnosis. Interpretation CC-Cruiser exhibited less accurate performance comparing to senior consultants in diagnosing childhood cataracts and making treatment decisions. However, the medical service provided by CC-Cruiser was less time-consuming and achieved a high level of patient satisfaction. CC-Cruiser has the capacity to assist human doctors in clinical practice in its current state. Funding National Key R&D Program of China (2018YFC0116500) and the Key Research Plan for the National Natural Science Foundation of China in Cultivation P...

The P2X 7 receptor is associated with the death of many cell types, and growing evidence supports its presence on neurons. Activation of the P2X 7 receptor on isolated retinal ganglion cells increases intracellular calcium levels and can kill the cells. Within the intact eye, however, glia and other cell types surrounding the ganglion cells may provide protection and attenuate the effects of receptor stimulation. This investigation thus asks whether stimulation of the P2X 7 receptor can actually kill retinal ganglion cells in vivo. Drugs were injected intravitreally into the superior/nasal region of Long Evans rats. Cell survival was determined by counting the number of remaining ganglion cells labeled with aminostilbamidine. The P2X 7 receptor agonist BzATP reduced ganglion cell survival as compared to eyes injected with saline solution. Ganglion cell death was inhibited by co-injection of the P2X 7 antagonists Brilliant Blue G and MRS 2540. The loss of ganglion cells following activation of the P2X 7 receptor was also prevented by the adenosine A 3 adenosine receptor agonist MRS 3558. In conclusion, stimulation of the P2X 7 receptor can kill retinal ganglion cells in vivo. The neuroprotective effects of A 3 activation identified in isolated ganglion cells are also receptor apparent in vivo. This implies that the balance between extracellular ATP and its protective metabolite adenosine can influence ganglion cell survival in the living eye.

Phlorizin exists in a number of fruits and foods and exhibits many bioactivities. The mechanism of its antidiabetic effect has been known as it can competitively inhibit sodium-glucose symporters (SGLTs). However, phlorizin has a wide range of two-phase metabolism in systemic circulation and shows poor oral bioavailability. An alternative mechanism may involve gut microbiota in intestine. Sixteen obese mice with type 2 diabetes (db/db) and eight age-matched control mice (db/+) were divided into three groups: diabetic group treated with phlorizin (DMT group), vehicle-treated diabetic group (DM group), and normal control group (CC group). Phlorizin was given in normal saline solution by intragastric administration for 10 weeks. After the last treatment course, body weight, energy intake, serum lipopolysaccharides (LPS), insulin resistance, and fecal short-chain fatty acids (SCFAs) were compared. 16S rRNA gene denaturing gradient gel electrophoresis (DGGE) and quantitative PCR were used to determine the changes in microbiome composition. Coadministration of phlorizin significantly prevented metabolic syndrome by decreasing weight gain, energy intake, serum lipopolysaccharides, and insulin resistance, and the fecal level of total SCFAs was dramatically increased, especially butyric acid. DGGE and quantitative PCR demonstrated that phlorizin coadministration increased the gut microbial diversity and the growth of Akkermansia muciniphila and Prevotella. Meanwhile, the gut microbiota structure of db/db mice after phlorizin treatment was improved and approached the normal group. The mechanism of the hypoglycemic action of phlorizin is associated with LPS decrease and gut microbiota changes; briefly, it acts in the intestine to modify gut microbial community structure, resulting in lower LPS load in the host and higher SCFAs producing beneficial bacteria.

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The A3 adenosine receptor is emerging as an important regulator of neuronal signaling, and in some situations receptor stimulation can limit excitability. As the NMDA receptor frequently contributes to neuronal excitability, this study examined whether A3 receptor activation could alter the calcium rise accompanying NMDA receptor stimulation. Calcium levels were determined from fura-2 imaging of isolated rat retinal ganglion cells as these neurons possess both receptor types. Brief application of glutamate or NMDA led to repeatable and reversible elevations of intracellular calcium. The A3 agonist Cl-IB-MECA reduced the response to both glutamate and NMDA. While adenosine mimicked the effect of Cl-IB-MECA, the A3 receptor antagonist MRS 1191 impeded the block by adenosine, implicating a role for the A3 receptor in the response to the natural agonist. The A1 receptor antagonist DPCPX provided additional inhibition, implying a contribution from both A1 and A3 adenosine receptors. The novel A3 agonist MRS 3558 (1’S,2’R,3’S,4’R,5’S)-4-(2-chloro-6-(3-chlorobenzylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0] hexane-1-carboxamide and mixed A1/A3 agonist MRS 3630 (1’S,2’R,3’S,4’R,5’S)-4-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo [3.1.0]hexane-1-carboxamide also inhibited the calcium rise induced by NMDA. Low levels of MRS 3558 were particularly effective, with an IC50 of 400 pM. In all cases, A3 receptor stimulation inhibited only 30-50% of the calcium rise. In summary, stimulation of the A3 adenosine receptor by either endogenous or synthesized agonists can limit the calcium rise accompanying NMDA receptor activation. It remains to be determined if partial block of the calcium rise by A3 agonists can modify downstream responses to NMDA receptor stimulation.