Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Immune-Related Hub Genes in Parkinson’s Disease

Background: Parkinson’s disease (PD) is a common, age-related, and progressive neurodegenerative disease. Growing evidence indicates that immune dysfunction plays an essential role in the pathogenic process of PD. The objective of this study was to explore potential immune-related hub genes and immune infiltration patterns of PD. Method: The microarray expression data of human postmortem substantia nigra samples were downloaded from GSE7621, GSE20141, and GSE49036. Key module genes were screened via weighted gene coexpression network analysis, and immune-related genes were intersected to obtain immune-key genes. Functional enrichment analysis was performed on immune-key genes of PD. In addition to, immune infiltration analysis was applied by a single-sample gene set enrichment analysis algorithm to detect differential immune cell types in the substantia nigra between PD samples and control samples. Least absolute shrinkage and selection operator analysis was performed to further identify immune-related hub genes for PD. Receiver operating characteristic curve analysis of the immune-related hub genes was used to differentiate PD patients from healthy controls. Correlations between immune-related hub genes and differential immune cell types were assessed. Result: Our findings identified four hub genes (SLC18A2, L1CAM, S100A12, and CXCR4) and seven immune cell types (neutrophils, T follicular helper cells, myeloid-derived suppressor cells, type 1 helper cells, immature B cells, immature dendritic cells, and CD56 bright natural killer cells). The area under the curve (AUC) value of the four-gene-combined model was 0.92. The AUC values of each immune-related hub gene (SLC18A2, L1CAM, S100A12, and CXCR4) were 0.81, 0.78, 0.78, and 0.76, respectively. Conclusion: In conclusion, SLC18A2, L1CAM, S100A12, and CXCR4 were identified as being associated with the pathogenesis of PD and should be further researched.
Combining Metabolic Engineering and Multiplexed Screening Methods for 3-Hydroxypropionic Acid Production in Pichia pastoris

Production of 3-hydroxypropionic acid (3-HP) in Pichia pastoris (syn. Komagataella phaffii) via the malonyl-CoA pathway has been recently demonstrated using glycerol as a carbon source, but the reported metrics were not commercially relevant. The flux through the heterologous pathway from malonyl-CoA to 3-HP was hypothesized as the main bottleneck. In the present study, different metabolic engineering approaches have been combined to improve the productivity of the original 3-HP producing strains. To do so, an additional copy of the gene encoding for the potential rate-limiting step of the pathway, i.e., the C-terminal domain of the malonyl-CoA reductase, was introduced. In addition, a variant of the endogenous acetyl-CoA carboxylase (ACC1 S1132A ) was overexpressed with the aim to increase the delivery of malonyl-CoA. Furthermore, the genes encoding for the pyruvate decarboxylase, aldehyde dehydrogenase and acetyl-CoA synthase, respectively, were overexpressed to enhance conversion of pyruvate into cytosolic acetyl-CoA, and the main gene responsible for the production of the by-product D-arabitol was deleted. Three different screening conditions were used to classify the performance of the different strains: 24-deep-well plates batch cultures, small-scale cultures in falcon tubes using FeedBeads® (i.e., slow release of glycerol over time), and mini bioreactor batch cultures. The best two strains from the FeedBeads® screening, PpHP8 and PpHP18, were tested in bioreactor fed-batch cultures using a pre-fixed exponentially increasing feeding rate. The strain PpHP18 produced up to 37.05 g L−1 of 3-HP at 0.712 g L−1 h−1 with a final product yield on glycerol of 0.194 Cmol−1 in fed-batch cultures. Remarkably, PpHP18 did not rank among the 2-top producer strains in small scale batch cultivations in deep-well plates and mini bioreactors, highlighting the importance of multiplexed screening conditions for adequate assessment of metabolic engineering strategies. These results represent a 50% increase in the product yield and final concentration, as well as over 30% increase in volumetric productivity compared to the previously obtained metrics for P. pastoris. Overall, the combination of glycerol as carbon source and a metabolically engineered P. pastoris strain resulted in the highest 3-HP concentration and productivity reported so far in yeast.
Chronic histiocytic intervillositis (CHI): current treatments and perinatal outcomes, a systematic review and a meta-analysis

Background Chronic histiocytic intervillositis (CHI) is a rare placental lesion with a high recurrence rate and poor perinatal outcomes. There are currently limited guidelines regarding the diagnosis of this condition in the index pregnancy and treatment where recurrence is suspected. Objective The primary objective of this systematic review and meta-analysis was to determine the perinatal outcomes of pregnancies affected by chronic histiocytic intervillositis and to what extent they can be improved with treatment. The secondary objective was to assess the relationship between CHI lesion severity and pregnancy loss. Methods A systematic search of Ovid Embase, Web of Science, Science Direct, PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. Case reports, cohort, case-control and randomised controlled trials (RCT) detailing the perinatal outcomes of CHI pregnancies, both treated and untreated, were included. Results No RCTs were identified. However, in a review population of 659 pregnancies, with additional 7 in case reports, CHI treatments included aspirin, prednisone, prednisolone, low molecular weight heparin (LMWH), hydroxychloroquine and adalimumab. A descriptive synthesis of data found mixed results for treatments in relation to live birth, miscarriage and fetal growth restriction outcomes. Furthermore, quantitative synthesis of 38 pregnancies revealed a non-significant improvement in live birth rate with CHI targeted treatment (OR 1.79 [95% CI 0.33-9.61] (p=0.50), while meta-analysis of CHI severity in line with pregnancy loss, in a sample of 231 pregnancies, revealed lower odds of pregnancy loss with less severe lesions (OR: 0.17 [0.03-0.80], p=0.03). Conclusions This systematic review and meta-analysis reinforce notions surrounding the insufficient evidence for CHI treatment. It also strengthens previous hypotheses detailing the positive association between CHI lesion severity and odds of pregnancy loss. Aspirin, LMWH, prednisolone, hydroxychloroquine and adalimumab are candidates with varying levels of weak to moderate evidence supporting their use. Further prospective research is required to obtain robust evidence pertaining to treatment safety and efficacy and optimal drug regimes. Systematic Review Registration [website], identifier CRD42021237604
Enhanced weathering potentials—the role of in situ CO2 and grain size distribution

The application of rock powder on agricultural land to ameliorate soils and remove carbon dioxide (CO2) from the air by chemical weathering is still subject to many uncertainties. To elucidate the effects of grain size distribution and soil partial pressure of carbon dioxide (pCO2) levels on CO2 uptake rates, two simple column experiments were designed and filled nearly daily with an amount of water that simulates humid tropical conditions, which prevail in areas known for being hotspots of weathering. Multiple materials (dunite, basanite, agricultural oxisol, a combination of the latter two, and loess) were compared under ambient and 100% CO2 atmosphere. In a second series, single material columns (dunite) were filled with three different grain size distributions. Total alkalinity, pH, major ions, and dissolved silica were determined in the outflow water of the columns for about 300 days. Under ambient atmospheric conditions, the CO2 consumption was the lowest in the oxisol column, with 100 t CO2 km−2 year−1, while dunite and basanite showed similar consumption rates (around 220 t CO2 km−2 year−1). The values are comparable to high literature values for ultramafic lithologies. Interestingly, the mixture of basanite and oxisol has a much higher consumption rate (around 430 t CO2 km−2 year−1) than the basanite alone. The weathering fluxes under saturated CO2 conditions are about four times higher in all columns, except the dunite column, where fluxes are increased by a factor of more than eleven. Grain size distribution differences also play a role, with the highest grain surface area normalized weathering rates observed in the columns with coarser grains, which at first seems counterintuitive. Our findings point to some important issues to be considered in future experiments and a potential rollout of EW as a carbon dioxide removal method. Only in theory do small grain sizes of the spread-material yield higher CO2 drawdown potentials than coarser material. The hydrologic conditions, which determine the residence times in the pore space, i.e., the time available for weathering reactions, can be more important than small grain size. Saturated-CO2 column results provide an upper limit for weathering rates under elevated CO2.
NAT10 Maintains OGA mRNA Stability Through ac4C Modification in Regulating Oocyte Maturation

In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase(OGA) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA, we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein–coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a, Gm7788, Gm41780, Trpc7, Gm29036, and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.
Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation

Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity.
Synergistic photobiomodulation with 808-nm and 1064-nm lasers to reduce the β-amyloid neurotoxicity in the in vitro Alzheimer's disease models

Background In Alzheimer's disease (AD), the deposition of β-amyloid (Aβ) plaques is closely associated with the neuronal apoptosis and activation of microglia, which may result in the functional impairment of neurons through pro-inflammation and over-pruning of the neurons. Photobiomodulation (PBM) is a non-invasive therapeutic approach without any conspicuous side effect, which has shown promising attributes in the treatment of chronic brain diseases such as AD by reducing the Aβ burden. However, neither the optimal parameters for PBM treatment nor its exact role in modulating the microglial functions/activities has been conclusively established yet. Methods An inflammatory stimulation model of Alzheimer's disease (AD) was set up by activating microglia and neuroblastoma with fibrosis β-amyloid (fAβ) in a transwell insert system. SH-SY5Y neuroblastoma cells and BV2 microglial cells were irradiated with the 808- and 1,064-nm lasers, respectively (a power density of 50 mW/cm2 and a dose of 10 J/cm2) to study the PBM activity. The amount of labeled fAβ phagocytosed by microglia was considered to assess the microglial phagocytosis. A PBM-induced neuroprotective study was conducted with the AD model under different laser parameters to realize the optimal condition. Microglial phenotype, microglial secretions of the pro-inflammatory and anti-inflammatory factors, and the intracellular Ca2+ levels in microglia were studied in detail to understand the structural and functional changes occurring in the microglial cells of AD model upon PBM treatment. Conclusion A synergistic PBM effect (with the 808- and 1,064-nm lasers) effectively inhibited the fAβ-induced neurotoxicity of neuroblastoma by promoting the viability of neuroblastoma and regulating the intracellular Ca2+ levels of microglia. Moreover, the downregulation of Ca2+ led to microglial polarization with an M2 phenotype, which promotes the fAβ phagocytosis, and resulted in the upregulated expression of anti-inflammatory factors and downregulated expression of inflammatory factors.
Reduced Ca2+ transient amplitudes may signify increased or decreased depolarization depending on the neuromodulatory signaling pathway

Neuromodulators regulate neuronal excitability and bias neural circuit outputs. Optical recording of neuronal Ca2+ transients is a powerful approach to study the impact of neuromodulators on neural circuit dynamics. We are investigating the polymodal nociceptor ASH in Caenorhabditis elegans to better understand the relationship between neuronal excitability and optically recorded Ca2+ transients. ASHs depolarize in response to the aversive olfactory stimulus 1-octanol (1-oct) with a concomitant rise in somal Ca2+, stimulating an aversive locomotory response. Serotonin (5-HT) potentiates 1-oct avoidance through Gαq signaling, which inhibits L-type voltage-gated Ca2+ channels in ASH. Although Ca2+ signals in the ASH soma decrease, depolarization amplitudes increase because Ca2+ mediates inhibitory feedback control of membrane potential in this context. Here, we investigate octopamine (OA) signaling in ASH to assess whether this negative correlation between somal Ca2+ and depolarization amplitudes is a general phenomenon, or characteristic of certain neuromodulatory pathways. Like 5-HT, OA reduces somal Ca2+ transient amplitudes in ASH neurons. However, OA antagonizes 5-HT modulation of 1-oct avoidance behavior, suggesting that OA may signal through a different pathway. We further show that the pathway for OA diminution of ASH somal Ca2+ consists of the OCTR-1 receptor, the Go heterotrimeric G-protein, and the G-protein activated inwardly rectifying channels IRK-2 and IRK-3, and this pathway reduces depolarization amplitudes in parallel with somal Ca2+ transient amplitudes. Therefore, even within a single neuron, somal Ca2+ signal reduction may indicate either increased or decreased depolarization amplitude, depending on which neuromodulatory signaling pathways are activated, underscoring the need for careful interpretation of Ca2+ imaging data in neuromodulatory studies.
3D Cell Cultures: Evolution of an Ancient Tool for New Applications

Recently, research is undergoing a drastic change in the application of the animal model as a unique investigation strategy, considering an alternative approach for the development of science for the future. Although conventional monolayer cell cultures represent an established and widely used in vitro method, the lack of tissue architecture and the complexity of such a model fails to inform true biological processes in vivo. Recent advances in cell culture techniques have revolutionized in vitro culture tools for biomedical research by creating powerful three-dimensional (3D) models to recapitulate cell heterogeneity, structure and functions of primary tissues. These models also bridge the gap between traditional two-dimensional (2D) single-layer cultures and animal models. 3D culture systems allow researchers to recreate human organs and diseases in one dish and thus holds great promise for many applications such as regenerative medicine, drug discovery, precision medicine, and cancer research, and gene expression studies. Bioengineering has made an important contribution in the context of 3D systems using scaffolds that help mimic the microenvironments in which cells naturally reside, supporting the mechanical, physical and biochemical requirements for cellular growth and function. We therefore speak of models based on organoids, bioreactors, organ-on-a-chip up to bioprinting and each of these systems provides its own advantages and applications. All of these techniques prove to be excellent candidates for the development of alternative methods for animal testing, as well as revolutionizing cell culture technology. 3D systems will therefore be able to provide new ideas for the study of cellular interactions both in basic and more specialized research, in compliance with the 3R principle. In this review, we provide a comparison of 2D cell culture with 3D cell culture, provide details of some of the different 3D culture techniques currently available by discussing their strengths as well as their potential applications.
Effects of 6-Hydroxykaempferol: A Potential Natural Product for Amelioration of Tendon Impairment

Tendon impairment is a common injury associated with impairment of range of motion and pain. Currently, evidence has confirmed that natural herbs contribute to orthopedics and have shown excellent results in the clinical management of tendon impairment. Shujin Huoxue tablet (SHT) and its complex prescriptions are regularly used in tendon rupture therapy with positive results. This study aimed to discover the potential molecules that promote tendon healing. The Chinese traditional medicine system pharmacological database analysis platform (TCMSP) is the primary resource. The Traditional Chinese Medicine Integrated Database and Encyclopedia of Traditional Chinese Medicine database were used as secondary databases. The GeneCards database was used to search for reported tendinopathy-related genes by keywords. Functions of the targeted genes were analyzed using Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes. Protein–protein interaction information was extracted from the STRING database. Docking study, MTT assay, quantitative real-time PCR, and migration assays were performed to obtain a better understanding of the herbs according to cell function to test the basic pharmacological action in vitro. A total of 104 disease nodes, 496 target gene nodes, 35 ingredient nodes, and one drug node were extracted. According to the TCMSP database, 6-hydroxykaempferol, which reportedly promotes the proliferation of microvascular endothelial cells, is a molecule found in SHT. We found that it promoted the proliferation and migration of tendon fibroblasts and elevated tendon repair-related gene expression. Purified 6-hydroxykaempferol promoted the proliferation and migration of tendon fibroblasts and increased their mRNA expression in tendon proliferation.
Structural Connectivity in Down Syndrome and Alzheimer’s Disease

Down syndrome (DS) arises from the triplication of chromosome 21, which leads to an atypical neurodevelopment and the overproduction of the amyloid precursor protein, predisposing to early Alzheimer’s disease (AD). Not surprisingly, trisomy 21 is widely considered a model to study predementia stages of AD. After decades, in which neural loss was the main focus, research in AD is now moving toward understanding the neurodegenerative aspects affecting white matter. Motivated by the development of magnetic resonance imaging (MRI)-based diffusion techniques, this shift in focus has led to several exploratory studies on both young and older individuals with DS. In this review, we synthesise the initial efforts made by researchers in characterising in-vivo structural connectivity in DS, together with the AD footprint on top of such pre-existing connectivity related to atypical brain development. The white matter structures found to be affected in DS are the corpus callosum and all the main long-association fibres, namely the inferior fronto-occipital fasciculus, the inferior and superior longitudinal fasciculus, the uncinate fasciculus and the cingulum bundle. Furthermore, the cingulum bundle and the corpus callosum appear to be particularly sensitive to early AD changes in this population. Findings are discussed in terms of their functional significance, alongside methodological considerations and implications for future research.