Exploring the genetic causal association of TIMP3 on CKD and kidney function: a two-sample mendelian randomization

Background: Numerous studies have demonstrated a positive association between the level of tissue inhibitor of metalloproteinase 3 (TIMP3) and chronic kidney disease (CKD). Nevertheless, whether those associations reflect causal links still to be determined. This study intended to research the causal relationship of TIMP3 with CKD and markers of kidney function, such as creatinine‐based estimated glomerular filtration rate (eGFRcrea), cystatin C‐based estimated glomerular filtration rate (eGFRcys), eGFRcrea in diabetics (eGFRcrea (DM)) and eGFRcrea in non diabetics (eGFRcrea (No DM)).Methods: In this study, we investigated the causal relationships between TIMP3 and CKD and kidney function markers using a two-sample Mendelian randomization (MR) technique. We used summary level datasets for TIMP3 and CKD from genome-wide association studies that we were able to access through the study by Suhre K and Pattaro C.Results: We found that TIMP3 had a significant positive causal effect on the risk of CKD (Inverse variance weighted (IVW):odds ratio (OR):0.962, 95% confidence interval (CI): (0.936-0.988),P:0.005). However TIMP3 levels had no significant effect on risk of eGFRcys (PIVW: 0.114),eGFRcrea (PIVW:0.333). After grouping patients based on their diabetes status, we found that genetically higher levels of TIMP3 had a significant impact on eGFRcrea in participants without diabetes (OR:1.003,95%CI (1.001-1.006),P IVW:0.007), but not in participants with diabetes (PIVW = 0.057). Heterogeneity and pleiotropy analyses were carried out to verify the accuracy of the MR findings. Their findings were all not statistically significant.Conclusion: Our study suggests that TIMP3 may be causally associated with CKD and eGFRcrea (No DM)in people of European ancestry. Strategies aimed to increase TIMP3 levels may provide new ways to delay the deterioration of renal function

Prevalence and associated factors of apathy in Chinese ALS patients

ObjectivveThis study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients.MethodsA total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke’s Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model.ResultsThe prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region (p = 0.027), ALSFRS-R score (p = 0.007), depression (p = 0.001) and anxiety (p < 0.001). Apathy had a significant negative effect on survival in ALS patients (p = 0.032).ConclusionApathy is relatively common (28.9%) in Chinese patients with ALS. Apathy is related to both the severity of the disease, and the presentation of non-motor symptoms in ALS, such as depression and anxiety disorders. Apathy is an independent prognostic factor for survival and requires early intervention and management

Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients

BackgroundCystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.MethodsA total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan–Meier curve and Cox regression model were used for survival analysis.ResultsCysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = −0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012–1.433). However, when treatment was included in the model, the result was no longer significant.ConclusionCysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention

Comparative transcriptome analysis reveals gene network regulation of TGase-induced thermotolerance in tomato

Transglutaminase (TGase), the ubiquitous protein in plants, catalyzes the post-translational transformation of proteins and plays a vital role in photosynthesis. However, its role and mechanism in tomato subjected to heat stress still remain unknown. Here, we carried out a transcriptomic assay to compare the differentially expressed genes (DEGs) between wild type (WT) and TGase overexpression (TGaseOE) plants employed to high-temperature at 42 °C and samples were collected after 0, 6, and 12 h, respectively. A total of 11,516 DEGs were identified from heat-stressed seedlings, while 1,148 and 1,353 DEGs were up-and down-regulated, respectively. The DEGs upon high-temperature stress were closely associated with the pathways encompassing protein processing in the endoplasmic reticulum, carbon fixation, and photosynthetic metabolism. In addition, 425 putative transcription factors (TFs) were identified, and the majority of them associated with the bHLH, HSF, AP2/ERF, MYB, and WRKY families. RNA-seq data validation further confirmed that 8 genes were linked to protein processing and photosynthesis, and the mRNA level of these genes in TGaseOE was higher than that in WT plants, which is consistent in transcriptome results. In conclusion, these results reveal the transcriptional regulation between WT and TGaseOE in tomato under heat stress and shed light on a new dimension of knowledge of TGase-mediated thermotolerance mechanism at the molecular level

Evaluation of the effects of forest management strategies on carbon sequestration in evergreen broad-leaved (Phoebe bournei) plantation forests using FORECAST ecosystem model

In the context of global climate change, it is critical to study how different forest management practices affect forest carbon sequestration. This is especially important for forest managers and policy makers who will have to design and implement appropriate mitigation and adaptation strategies. Previous research has focused on coniferous plantations with rare examination of plantations of evergreen broadleaved species. Phoebe bournei (Hemsley) Yang, as one of the representative species of subtropical evergreen broadleaf forests in Asia, has a unique potential to increase forest carbon sink. In this study, field data were combined with the forest ecosystem management model FORECAST to estimate the impacts of different forest management strategies (combinations of planting densities from 1000 to 4000 trees ha-1, rotation lengths from 20 to 80 years, and different harvesting intensities: stem-only, whole-tree and complete-tree) on carbon sequestration of Phoebe bournei plantations in south-eastern China. Field and previously published data were used to calibrate the model for stand biomass pools accumulation, stand density and mortality, light response curves, photosynthetic efficiency, and data on soil nutrient pools, for three different site conditions. The results showed that the most suitable planting density to maximize carbon sequestration in Phoebe bournei plantations is 2000-3000 trees ha-1. Long rotations (80 years) are better than shorter rotations (20 or 30 years) for the long-term maintenance of site productivity, though the recommended rotation length for maximizing carbon sequestration and maintaining forest productivity is 40-60 years. As for harvesting intensity, stem-only harvesting is the most suitable strategy to manage for carbon sequestration when maintaining long-term site productivity, with whole-tree and complete-tree harvesting constituting less optimal options. Our modelling exercise indicates that Phoebe bournei plantations have great potential for carbon sequestration if they are managed under sustainable and ecologically-based strategies. Given that forests are important in the global carbon cycle, it is recommended that afforestation efforts in relevant sub-tropical regions use appropriate broad-leaved species that can help resolve ecological and socio-economic challenge

Impacts of Plastic Filming on Growth Environment, Yield Parameters and Quality Attributes of Lettuce

The condition of soil and microclimate are prerequisite for proper growth and development of a plant. The environment may be mediated by artificial filming with different colored polyethylene. The mechanism of lettuce growing under colored plastic film remains largely unknown. Thus, to investigate the impact of different plastic film on the growth environment, yield parameters and phytochemical properties of lettuce, the present study was performed. Five different colored polyethylene films viz. black, white, blue, olive and silver were used as a treatment factor, in filed condition. The results demonstrated that the soil pH, temperature and overall performance of lettuce, as well as the phytochemical composition, varied within the use of different films. The maximum soil pH and temperature were found under black filming plots. Additionally, the black colored plastic film exhibited the best values for most of the yield parameters studied over other plastic films, whereas the field with non-plastic film condition showed the worst data in the experiment. Phytochemical concentrations and nutritive value of lettuce were also significantly affected by the colored plastic treatments. Furthermore, the chlorophyll, anthocyanin, phenols and carotenoids contents were increased in plants grown in soil covered with black polyethylene. Vitamin C content was of 2.5 fold higher in the plants grown in the black film compared to control conditions. The application of plastic film led to elevated concentrations of macro and micronutrients in lettuce because of the direct effect of modified radiation under the plastic film. Taken together, it can be concluded that plastic filming could be used to enhance the yield and nutritional status of lettuce in natural plant production facilities

How Chromatin Is Remodelled during DNA Repair of UV-Induced DNA Damage in Saccharomyces cerevisiae

Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation–induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides important insight into how GG-NER operates in chromatin

DeepSeek LLM: Scaling Open-Source Language Models with Longtermism

The rapid development of open-source large language models (LLMs) has been truly remarkable. However, the scaling law described in previous literature presents varying conclusions, which casts a dark cloud over scaling LLMs. We delve into the study of scaling laws and present our distinctive findings that facilitate scaling of large scale models in two commonly used open-source configurations, 7B and 67B. Guided by the scaling laws, we introduce DeepSeek LLM, a project dedicated to advancing open-source language models with a long-term perspective. To support the pre-training phase, we have developed a dataset that currently consists of 2 trillion tokens and is continuously expanding. We further conduct supervised fine-tuning (SFT) and Direct Preference Optimization (DPO) on DeepSeek LLM Base models, resulting in the creation of DeepSeek Chat models. Our evaluation results demonstrate that DeepSeek LLM 67B surpasses LLaMA-2 70B on various benchmarks, particularly in the domains of code, mathematics, and reasoning. Furthermore, open-ended evaluations reveal that DeepSeek LLM 67B Chat exhibits superior performance compared to GPT-3.5