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BioRxiv : the Preprint Server For... Jun 2024In eukaryotic post-replicative mismatch repair, MutS homologs (MSH) detect mismatches and recruit MLH complexes to nick the newly replicated DNA strand upon activation...
In eukaryotic post-replicative mismatch repair, MutS homologs (MSH) detect mismatches and recruit MLH complexes to nick the newly replicated DNA strand upon activation by the replication processivity clamp, PCNA. This incision enables mismatch removal and DNA repair. Biasing MLH endonuclease activity to the newly replicated DNA strand is crucial for repair. In reconstituted assays, PCNA is loaded at pre-existing discontinuities and orients the major MLH endonuclease Mlh1-Pms1/MLH1-PMS2 (yeast/human) to nick the discontinuous strand. newly replicated DNA transiently contains discontinuities which are critical for efficient mismatch repair. How these discontinuities are preserved as strand discrimination signals during the window of time where mismatch repair occurs is unknown. Here, we demonstrate that yeast Mlh1-Pms1 uses ATP binding to recognize DNA discontinuities. This complex does not efficiently interact with PCNA, which partially suppresses ATPase activity, and prevents dissociation from the discontinuity. These data suggest that in addition to initiating mismatch repair by nicking newly replicated DNA, Mlh1-Pms1 protects strand discrimination signals, aiding in maintaining its own strand discrimination signposts. Our findings also highlight the significance of Mlh1-Pms1's ATPase activity for inducing DNA dissociation, as mutant proteins deficient in this function become immobilized on DNA post-incision, explaining phenotypes.
PubMed: 38915520
DOI: 10.1101/2024.06.13.598860 -
Frontiers in Microbiology 2024Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been...
Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been proposed as a potential cause of neurodegeneration. While studies have extensively tackled the interaction between autophagy and HSV-1 in neurons, research in glial cells is currently limited. Our studies demonstrate that HSV-1 inhibits, but not completely blocks, the formation of autophagosomes in human oligodendroglioma- and astrocytoma- derived cell lines. These findings have been confirmed in murine oligodendrocyte precursor cells (OPCs). Finally, this study investigates the impact of autophagy on HSV-1 infection in glial cells. While the lack of basal autophagy in LC3B knockout glial cells does not have a significant effect on viral infection, cells without the autophagy-related protein ATG5 exhibit reduced viral production. The absence of ATG5 leads to a decrease in the transcription and replication of viral genes, as well as a delay in the initial stages of the formation of HSV-1 replication compartments. These findings indicate that while autophagy may not play a significant role in antiviral defense in glial cells, HSV-1 may be inhibiting autophagy to exploit non-canonical functions of certain components of the autophagic machinery, such as ATG5, to benefit its lifecycle.
PubMed: 38915300
DOI: 10.3389/fmicb.2024.1411655 -
Ageing Research Reviews Jun 2024Caffeine is one of the most consumed psychoactive substances globally. Caffeine-gene interactions in Parkinson's disease (PD) has not been systematically examined. (Review)
Review
BACKGROUND
Caffeine is one of the most consumed psychoactive substances globally. Caffeine-gene interactions in Parkinson's disease (PD) has not been systematically examined.
OBJECTIVES
To conduct a systematic review on the interaction between caffeine consumption and genetic susceptibility to PD.
METHODOLOGY
We conducted PubMed and Embase search using terms "Genetic association studies", "Caffeine", "polymorphism" and "Parkinson's disease", from inception till 2023. Of the initial 2391 studies, 21 case control studies were included. The demographics, genetic and clinical data were extracted and analyzed.
RESULTS
We identified 21 studies which involved a total of 607,074 study subjects and 17 gene loci (SNCA, MAPT, HLA-DRA, NOS1, NOS3, GBA, ApoE, BST1, ESR2, NAT2, SLC2A13, LRRK2, NOS2A, GRIN2A, CYP1A2, ESR1, ADORA2A) have been investigated for the effect of gene-caffeine interaction and PD risk. The genes were identified through PD GWAS or involved in caffeine or related metabolism pathways. Based on the genetic association and interaction studies, only MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A have been shown by at least one study to have a positive caffeine-gene interaction influencing the risk of PD.
CONCLUSION
Studies have shown an interaction between caffeine with genetic variants of MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A in modulating the risk of PD. Due to the potential limitations of these discovery/pilot studies, further independent replication studies are needed. Better designed genetic association studies in multi-ancestry and admixed cohorts to identify potential shared or unique multivariate gene-environmental interactions, as well as functional studies of gene-caffeine interactions will be useful.
PubMed: 38914264
DOI: 10.1016/j.arr.2024.102381 -
Fish & Shellfish Immunology Jun 2024As an environmentally friendly alternative to antibiotics, bee venom holds promise for aquaculture due to its diverse health advantages, including immune-amplifying and...
As an environmentally friendly alternative to antibiotics, bee venom holds promise for aquaculture due to its diverse health advantages, including immune-amplifying and anti-inflammatory features. This study investigated the effects of dietary bee venom (BV) on the growth and physiological performance of Thinlip mullet (Liza ramada) with an initial body weight of 40.04 ± 0.11 g for 60 days. Fish were distributed to five dietary treatments (0, 2, 4, 6, and 8 mg BV/kg diet) with three replicates. Growth traits, gut enzyme ability (lipase, protease, amylase), intestinal and liver histology, blood biochemistry, immune responses [lysozyme activity (LYZ), bactericidal activity (BA), nitroblue tetrazolium (NBT%)], and antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malondialdehyde (MDA)] were evaluated. BV supplementation significantly improved growth performance, digestive enzyme activity, histological integrity of organs, immune responses (LYZ, BA), and antioxidant status (SOD, CAT, GPx), while declining MDA levels. Optimal BV levels were identified between 4.2 and 5.8 mg/kg diet for different parameters. Overall, the findings suggest that BV supplementation can enhance growth and physiological performance in Thinlip mullet, highlighting its potential as a beneficial dietary supplement for fish health and aquaculture management.
PubMed: 38914180
DOI: 10.1016/j.fsi.2024.109713 -
Environmental Science and Pollution... Jun 2024Use of waste wood biomass for bioenergy produces wood ash as a by-product; this ash is typically landfilled, but can potentially play an important role in soil...
Use of waste wood biomass for bioenergy produces wood ash as a by-product; this ash is typically landfilled, but can potentially play an important role in soil improvement and forest restoration. In particular, high-carbon wood ash biochar (HCWAB) could supply nutrients, improve substrate water-holding capacity and pH, and emulate the ecosystem benefits of wildfire residues. Thickened tailings sites at metal mines across Canada are subject to stringent restoration regulations that entail planting of native trees to promote rapid reforestation. While HCWAB may prove beneficial in this context, field trials have been very limited to date. We conducted a large-scale, replicated field trial on sand-capped tailings at an operational gold mine in the Canadian boreal forest to assess the impact of HCWAB (at dosages of 0, 6.4, 12.8, and 19.1 t/ha) on survival and growth of four native tree species, as well as substrate chemical properties and element uptake in tree tissues. After 2 years, the survival of planted, native trees was highest at low to moderate application rates; HCWAB dosages above 13 t/ha presented reduced tree survival to levels comparable to unamended substrates. Tree growth was higher across all HCWAB doses relative to growth in samples planted on untreated substrates; tree species and initial size also had large impacts on final tree survival and aboveground growth. The survival of Betula papyrifera was significantly higher than other species, while smaller transplanted trees in general survived in greater numbers compared to larger size classes. Volunteer herbaceous vegetation significantly increased at the higher HCWAB application dosages and tree performance was negatively correlated with vegetation cover, consistent with a resource competition effect. HCWAB additions to sand-capped mine tailings did not significantly alter tree tissue concentrations or substrate availability of potentially toxic metals (Cd, Cu, Al). We conclude that low to moderate dosages of HCWAB on sand-capped tailings, particularly between 6.4 and 12.8 t/ha, may offer benefits to early tree survival, growth, and substrate nutrient status without causing significant risks of phytotoxicity and recommend future field trials focus on strategies to reduce tree competition with competing vegetation.
PubMed: 38910184
DOI: 10.1007/s11356-024-33962-y -
Journal of Equine Veterinary Science Jun 2024Mastication is the initial phase of digestion and is crucial to equine health due to its role in saliva production and food particle reduction. Hay nets have been...
Mastication is the initial phase of digestion and is crucial to equine health due to its role in saliva production and food particle reduction. Hay nets have been promoted to slow the rate of hay consumption, with many styles of slow feeders available. Limited research has shown that nets may slow consumption, but no research has examined their effect on the horse's chewing frequency and patterns. The objective of this study was to compare chew frequency (CF, total number of chews/kg consumed) and chew duration (CD, total minutes chewed/kg consumed), as well as distribution of chews over a feeding period, of horses eating bermudagrass hay in three styles of hay nets [large mesh (LM), small mesh (SM), bottom hole (BH)] as compared to a control of loose hay (CTL). Treatments were assigned in a replicated Latin square 4 × 4 using eight horses. Horses were given a 24-hr acclimation period prior to recording their chewing patterns over a 24-hr period using an automated halter fit with a pressure-sensor noseband. Results indicate that CF was not influenced by treatment. However, SM resulted in longer CD as compared to CTL (P=0.007). Additionally, BH resulted in a higher percentage of chews completed in the first 240 min compared to SM (P=0.039), indicating more rapid consumption. Results of this study indicate hay nets may not influence the number of chews a horse performs while masticating hay, but small mesh feeders may increase the CD and reduce early consumption rate.
PubMed: 38908808
DOI: 10.1016/j.jevs.2024.105133 -
Environmental Research Jun 2024To investigate the inhibitory effects of various transition metal ions on nitrogen removal and their underlying mechanisms, the single and combined effects of Cu Ni and...
To investigate the inhibitory effects of various transition metal ions on nitrogen removal and their underlying mechanisms, the single and combined effects of Cu Ni and Zn on Heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria Acinetobacter sp. TAC-1 were studied in a batch experiment system. The results revealed that increasing concentrations of Cu and Ni had a detrimental effect on the removal of ammonium nitrogen (NH-N) and total nitrogen (TN). Specifically, Cu concentration of 10 mg/L, the TN degradation rate was 55.09%, compared to 77.60% in the control group. Cu exhibited a pronounced inhibitory effect. In contrast, Zn showed no apparent inhibitory effect on NH-N removal and even enhanced TN removal at lower concentrations. However, when the mixed ion concentration of Zn+Ni exceeded 5 mg/L, the removal rates of NH-N and TN were significantly reduced. Moreover, transition metal ions did not significantly impact the removal rates of chemical oxygen demand (COD). The inhibition model fitting results indicated that the inhibition sequence was Cu > Zn > Ni. Transcriptome analysis demonstrated that metal ions influence TAC-1 activity by modulating the expression of pivotal genes, including zinc ABC transporter substrate binding protein (znuA), ribosomal protein (rpsM), and chromosome replication initiation protein (dnaA) and DNA replication of TAC-1 under metal ion stress, leading to disruptions in transcription, translation, and cell membrane structure. Finally, a conceptual model was proposed by us to summarize the inhibition mechanism and possible response strategies of TAC-1 bacteria under metal ion stress, and to address the lack of understanding regarding the influence mechanism of TAC-1 on nitrogen removal in wastewater co-polluted by metal and ammonia nitrogen. The results provided practical guidance for the management of transition metal and ammonia nitrogen co-polluted water bodies, as well as the removal of high nitrogen.
PubMed: 38906451
DOI: 10.1016/j.envres.2024.119460 -
Journal of Chemical Theory and... Jun 2024One of the key challenges of -means clustering is the seed selection or the initial centroid estimation since the clustering result depends heavily on this choice....
One of the key challenges of -means clustering is the seed selection or the initial centroid estimation since the clustering result depends heavily on this choice. Alternatives such as -means++ have mitigated this limitation by estimating the centroids using an empirical probability distribution. However, with high-dimensional and complex data sets such as those obtained from molecular simulation, -means++ fails to partition the data in an optimal manner. Furthermore, stochastic elements in all flavors of -means++ will lead to a lack of reproducibility. -means -Ary Natural Initiation (NANI) is presented as an alternative to tackle this challenge by using efficient -ary comparisons to both identify high-density regions in the data and select a diverse set of initial conformations. Centroids generated from NANI are not only representative of the data and different from one another, helping -means to partition the data accurately, but also deterministic, providing consistent cluster populations across replicates. From peptide and protein folding molecular simulations, NANI was able to create compact and well-separated clusters as well as accurately find the metastable states that agree with the literature. NANI can cluster diverse data sets and be used as a standalone tool or as part of our MDANCE clustering package.
PubMed: 38905589
DOI: 10.1021/acs.jctc.4c00308 -
Frontiers in Genetics 2024The recognition of DNA Binding Proteins (DBPs) plays a crucial role in understanding biological functions such as replication, transcription, and repair. Although...
The recognition of DNA Binding Proteins (DBPs) plays a crucial role in understanding biological functions such as replication, transcription, and repair. Although current sequence-based methods have shown some effectiveness, they often fail to fully utilize the potential of deep learning in capturing complex patterns. This study introduces a novel model, LGC-DBP, which integrates Long Short-Term Memory (LSTM), Gated Inception Convolution, and Improved Channel Attention mechanisms to enhance the prediction of DBPs. Initially, the model transforms protein sequences into Position Specific Scoring Matrices (PSSM), then processed through our deep learning framework. Within this framework, Gated Inception Convolution merges the concepts of gating units with the advantages of Graph Convolutional Network (GCN) and Dilated Convolution, significantly surpassing traditional convolution methods. The Improved Channel Attention mechanism substantially enhances the model's responsiveness and accuracy by shifting from a single input to three inputs and integrating three sigmoid functions along with an additional layer output. These innovative combinations have significantly improved model performance, enabling LGC-DBP to recognize and interpret the complex relationships within DBP features more accurately. The evaluation results show that LGC-DBP achieves an accuracy of 88.26% and a Matthews correlation coefficient of 0.701, both surpassing existing methods. These achievements demonstrate the model's strong capability in integrating and analyzing multi-dimensional data and mark a significant advancement over traditional methods by capturing deeper, nonlinear interactions within the data.
PubMed: 38903752
DOI: 10.3389/fgene.2024.1411847 -
BioRxiv : the Preprint Server For... Jun 2024Evolutionary arms races can arise at the contact surfaces between host and viral proteins, producing dynamic spaces in which genetic variants are continually pursued....
Evolutionary arms races can arise at the contact surfaces between host and viral proteins, producing dynamic spaces in which genetic variants are continually pursued. However, the sampling of genetic variation must be balanced with the need to maintain protein function. A striking case is given by protein kinase R (PKR), a member of the mammalian innate immune system. PKR detects viral replication within the host cell and halts protein synthesis to prevent viral replication by phosphorylating eIF2α, a component of the translation initiation machinery. PKR is targeted by many viral antagonists, including poxvirus pseudosubstrate antagonists that inhibit PKR by interacting with the same binding surface as eIF2α. Remarkably, PKR has several rapidly evolving residues at this interface, suggesting it is engaging in an evolutionary arms race, despite the surface's critical role in phosphorylating eIF2α. To systematically explore the evolutionary opportunities available at this dynamic interface, we generated and characterized a library of 426 SNP-accessible nonsynonymous variants of human PKR for their ability to escape inhibition by the model pseudosubstrate inhibitor K3 from vaccinia virus. We identified key sites in the PKR kinase domain that harbor K3-resistant variants, as well as critical sites where variation leads to loss of function. We find K3-resistant variants are readily available throughout the interface and are enriched at sites under positive selection. Moreover, variants beneficial against K3 were also beneficial against an enhanced variant of K3, indicating resilience to viral adaptation. Overall, we find that the eIF2α-binding surface of PKR is highly malleable, potentiating its evolutionary ability to combat viral inhibition.
PubMed: 38903081
DOI: 10.1101/2024.05.29.596416