Roles of PI3K and JAK pathways in viability of retinal ganglion cells after acute elevation of intraocular pressure in rats with different autoimmune backgrounds

<p>Abstract</p> <p>Background</p> <p>We recently showed that whereas inhibition of PI3K/akt or JAK/STAT pathway promoted retinal ganglion cell (RGC) survival after optic nerve (ON) injury in Fischer 344 (F344) rats, the same inhibition resulted in aggravated RGC loss after acute intraocular pressure (IOP) elevation in Sprague Dawley (SPD) rats. In addition, the responses of macrophages to ON injury and acute IOP elevation were different between F344 and Lewis rats, i.e., different autoimmune profiles. Using an acute IOP elevation paradigm in this study, we investigated 1) whether autoimmune background influences PI3K/akt and JAK/STAT functions by examining the effect of PI3K/akt and JAK/STAT pathway inhibition on RGC survival in F344 and Lewis rats, and 2) whether differential actions of macrophages occur in PI3K/akt and JAK/STAT pathways-dependent modulation of RGC survival. IOP elevation was performed at 110 mmHg for 2 hours. PI3K/akt and JAK/STAT pathway inhibitors were applied intravitreally to block their respective pathway signaling transduction. Because macrophage invasion was seen in the eye after the pathway inhibition, to examine the role of these pathways independent of macrophages, macrophages in the retina were removed by intravitreal application of clodronate liposomes. Viable RGCs were retrogradely labelled by FluoroGold 40 hours before animal sacrifice.</p> <p>Results</p> <p>Similar to what was previously observed, significantly more RGCs were lost in Lewis than F344 rats 3 weeks after acute IOP elevation. As in SPD rats, inhibition of the PI3K/akt or JAK/STAT pathway increased the loss of RGCs in both F344 and Lewis rats. Removal of macrophages in the eye by clodronate liposomes reduced RGC loss due to pathway inhibition in both strains.</p> <p>Conclusion</p> <p>This study demonstrates that following acute IOP elevation 1) PI3K/akt and JAK/STAT pathways mediate RGC survival in both F344 and Lewis rats, 2) autoimmune responses do not influence the functions of these two pathways, and 3) PI3K/akt and JAK/STAT pathway inhibition-dependent activation of macrophages is detrimental to RGCs.</p

Up-Regulation of Th17 Cells May Underlie Inhibition of Treg Development Caused by Immunization with Activated Syngeneic T Cells

BACKGROUND: Our previous work showed that mice immunized with attenuated activated syngeneic T cells (aTCV) led to damping Treg function which resulted in enhancing anti-tumor immunity. It is well known that DC plays a very important role in controlling Th cell differentiation; whether DC involves Treg attenuation in immunized mice remained unknown. In this study, we provided evidence that increased mature DC (mDC) after immunization with aTCV skewed Th17 differentiation, which resulted in inhibition of Treg differentiation through IL-6 signaling pathway. PRINCIPAL FINDINGS: In the present study, we found that the frequency of mDCs increased dramatically in the immunized mice accompanied by lower Treg cells compared to the controls. Moreover, both DCs and serum derived from the immunized mice suppressed Treg differentiation in vitro, respectively. mDCs generated from bone marrow precursor cells in vitro strongly inhibited Treg development and simultaneously drove Th17 differentiation with elevated IL-6 production. However, PD-L1, a potent Treg inducer did not show effect on Treg down-regulation. Assay with transwell systems showed that cell-cell contact was necessary for IL-6 production to a threshold to activate Th17 transcriptional factor RORγt and to inhibit Treg counterpart Foxp3. CONCLUSIONS: Our results implicate up-regulated Th17 development might be one of mechanisms of enhancing anti-tumor immunity induced by immunization with aTCV, which provide a novel insight in numerous mechanisms responsible for anti-tumor immunity

Chinese eye exercises and myopia development in school age children: a nested case-control study

Chinese eye exercises have been implemented in China as an intervention for controlling children’s myopia for over 50 years. This nested case-control study investigated Chinese eye exercises and their association with myopia development in junior middle school children. Outcome measures were the onset and progression of myopia over a two-year period. Cases were defined as 1. Myopia onset (cycloplegic spherical equivalent ≤ −0.5 diopter in non-myopic children). 2. Myopia progression (myopia shift of ≥1.0 diopter in those who were myopic at baseline). Two independent investigators assessed the quality of Chinese eye exercises performance at the end of the follow-up period. Of 260 children at baseline (mean age was 12.7 ± 0.5 years), 201 were eligible for this study. There was no association between eye exercises and the risk of myopia-onset (OR = 0.73, 95%CI: 0.24–2.21), nor myopia progression (OR = 0.79, 95%CI: 0.41–1.53). The group who performed high quality exercises had a slightly lower myopia progression of 0.15 D than the children who did not perform the exercise over a period of 2 years. However, the limited sample size, low dosage and performance quality of Chinese eye exercises in children did not result in statistical significance and require further studies

Metabolic Pathways Involved in Carbon Dioxide Enhanced Heat Tolerance in Bermudagrass

Global climate changes involve elevated temperature and CO2 concentration, imposing significant impact on plant growth of various plant species. Elevated temperature exacerbates heat damages, but elevated CO2 has positive effects on promoting plant growth and heat tolerance. The objective of this study was to identify metabolic pathways affected by elevated CO2 conferring the improvement of heat tolerance in a C4 perennial grass species, bermudagrass (Cynodon dactylon Pers.). Plants were planted under either ambient CO2 concentration (400 μmol⋅mol-1) or elevated CO2 concentration (800 μmol⋅mol-1) and subjected to ambient temperature (30/25°C, day/night) or heat stress (45/40°C, day/night). Elevated CO2 concentration suppressed heat-induced damages and improved heat tolerance in bermudagrass. The enhanced heat tolerance under elevated CO2 was attributed to some important metabolic pathways during which proteins and metabolites were up-regulated, including light reaction (ATP synthase subunit and photosystem I reaction center subunit) and carbon fixation [(glyceraldehyde-3-phosphate dehydrogenase, GAPDH), fructose-bisphosphate aldolase, phosphoglycerate kinase, sedoheptulose-1,7-bisphosphatase and sugars) of photosynthesis, glycolysis (GAPDH, glucose, fructose, and galactose) and TCA cycle (pyruvic acid, malic acid and malate dehydrogenase) of respiration, amino acid metabolism (aspartic acid, methionine, threonine, isoleucine, lysine, valine, alanine, and isoleucine) as well as the GABA shunt (GABA, glutamic acid, alanine, proline and 5-oxoproline). The up-regulation of those metabolic processes by elevated CO2 could at least partially contribute to the improvement of heat tolerance in perennial grass species

SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma

Purpose: To investigate the associations between gene variants in cholesterol 24S-hydroxylase (CYP46A1), LIM homeobox transcription factor 1-beta (LMX1B), plexin domain containing 2 (PLXDC2), toll-like receptor 4 (TLR4), transmembrane and tetratricopeptide repeat containing 2 (TMTC2), zona pellucida glycoprotein 4 (ZP4), chromosome 2p16.3, and primary open-angle glaucoma (POAG). Methods: We studied 462 POAG patients and 577 controls from three cohorts (Hong Kong, Shantou, and Beijing, China). Twelve single-nucleotide polymorphisms (SNPs) were genotyped in the Hong Kong cohort using TaqMan genotyping assay. Significant associations were validated in the Shantou and Beijing cohorts. Results: Association of POAG with TLR4 rs7037117, in a recessive model, was identified in the Hong Kong and Shantou cohorts (both southern Chinese, $p_{rec}$=0.0019) but not the Beijing cohort (northern Chinese). rs1533428 at chromosome 2p16.3 showed a consistent trend of age-specific association in all three cohorts. Genotypes TT + CT conferred a 2.16 fold of significantly increased risk to late-onset POAG ($p_{dom}$=0.00025), but no significant risk to POAG of younger ages of onset in the combined cohort. A joint effect was found between rs7037117 and rs1533428, with carriers of both higher-risk genotypes having a 4.53 fold of increased disease risk (p=0.00028). Conclusions: Our study reveals discrepant association patterns of 12 candidate SNPs in 7 genes/loci with POAG in Chinese, provides positive replications for POAG markers rs1533428 at 2p16.3 and TLR4 rs7037117, and suggests that rs1533428 is a putative risk variant for late-onset POAG. The identification of an age-specific association between rs1533428 and late-onset POAG highlights a new genotype-phenotype association in POAG. Further studies are warranted to confirm the age-specific association

Large AI Models in Health Informatics: Applications, Challenges, and the Future

Large AI models, or foundation models, are models recently emerging with massive scales both parameter-wise and data-wise, the magnitudes of which can reach beyond billions. Once pretrained, large AI models demonstrate impressive performance in various downstream tasks. A prime example is ChatGPT, whose capability has compelled people's imagination about the far-reaching influence that large AI models can have and their potential to transform different domains of our lives. In health informatics, the advent of large AI models has brought new paradigms for the design of methodologies. The scale of multi-modal data in the biomedical and health domain has been ever-expanding especially since the community embraced the era of deep learning, which provides the ground to develop, validate, and advance large AI models for breakthroughs in health-related areas. This article presents a comprehensive review of large AI models, from background to their applications. We identify seven key sectors in which large AI models are applicable and might have substantial influence, including 1) bioinformatics; 2) medical diagnosis; 3) medical imaging; 4) medical informatics; 5) medical education; 6) public health; and 7) medical robotics. We examine their challenges, followed by a critical discussion about potential future directions and pitfalls of large AI models in transforming the field of health informatics.Comment: This article has been accepted for publication in IEEE Journal of Biomedical and Health Informatic

Perbandingan Perhitungan Trafik Jam Sibuk CDMA 2000 1x Pada BTS Inner City Dan BTS Outer City Dengan Mempergunakan Metode ADPH, TCBH, FDMH Dan FDMP

Cellular communication system is a wireless communication system where the subscriber can move within a wide network coverage. Code Division Multiple Access (CDMA) is a multiuser access technology that is each user uses a unique code contained in the access channel in the system. Calculation and determination of peak hours can be done by several methods such as: Average Daily Peak Hour (ADPH), Time Consistent Busy Hour (TCBH), Fixed Daily Measurement Hour (FDMH), Fixed Daily Measurement Period (FDMP). The effectiveness of the channel should be determined by occupancy both at inner city territory and outer city &nbsp;territory location. Using design Erlang (Erl) for supply channel at Base Transceiver Station (BTS) that provided, BTS has a design Erlang of 369,83 Erl at inner city and it has a design Erlang of 241,8 Erl at outer city. Peak hour on the inner city occurred at 12:00 to 15:00, whereas the outer city of peak hour occurred at 18:00 to 21:00. Effectiveness value that determined by operator are : &lt;20% = low occupancy (not effective), 21% to 69% = normal occupancy (effective), and &gt; 70% = high occupancy (very effective). In this case occupancy values obtained in each method is between 21% to 69% which means effectiv