Miracle-dz/UniFAR-FTUs huggingface dataset:
CMTM6 mediates cisplatin resistance in OSCC by regulating AKT/c-MYC driven ribosome biogenesis

CMTM6, a type 3 transmembrane protein, is known to stabilize the expression of programmed cell death ligand 1 (PD-L1) and hence facilitates the immune evasion of tumor cells. Recently, we demonstrated that CMTM6 is a major driver of cisplatin resistance in oral squamous cell carcinomas (OSCC). However, the detailed mechanism how CMTM6 rewires cisplatin resistance in OSCC is yet to be explored. RNA sequencing analysis of cisplatin resistant OSCC lines stably expressing NtShRNA and CMTM6 ShRNA revealed that CMTM6 might be a potential regulator of ribosome biogenesis network. Knocking down CMTM6 significantly inhibited transcription of 47S precursor rRNA and hindered the nucleolar structure, indicating reduced ribosome biogenesis. When CMTM6 was ectopically over expressed in CMTM6KD cells, almost all ribosomal machinery components were rescued. Mechanistically, CMTM6 induced the expression of C-Myc, which promotes RNA polymerase I mediated rDNA transcription. In addition to this, CMTM6 also found to regulate the AKT–mTORC1-dependent ribosome biogenesis and protein synthesis in cisplatin resistant lines. The nude mice and zebrafish xenograft experiments indicate that blocking ribosome synthesis either by genetic inhibitor (CMTM6KD) or by pharmacological inhibitor (CX-5461), significantly restores cisplatin medicated cell death in chemoresistant OSCC. Overall, our study suggests that CMTM6 is a major regulator of ribosome biogenesis network and targeting ribosome biogenesis network is a viable target to overcome chemoresistance in OSCC. The novel combination of CX-5461 and cisplatin deserves further clinical investigation in advanced OSCC.
Identification of YAB11-NGAL1 controlling leaf serrations through enhanced genome-wide association studies of Populus

Leaf margins are complex plant morphological features and contribute to the diversity of leaf shapes which effect on plant structure, yield and adaptation. Although several regulators of leaf margins have been identified, the genetic basis of natural variation therein has not been fully elucidated. We first profiled two distinct types (serration and smooth) of leaf morphology using the persistent homology mathematical framework (PHMF) in poplar. Combined genome-wide association studies (GWAS) and expression quantitative trait nucleotide (eQTN) mapping to create a module of leaf morphology controlling using data from Populus tomentosa and P. simonii association population, respectively. Natural variation of leaf margins is associated with transcript abundances of YABBY11 (YAB11) in poplar. In P. tomentosa, PtoYAB11 carries premature stop codon (PtoYAB11PSC) resulting in lost its positive regulation in PtoNGAL-1, PtoRBCL, PtoATPA, PtoATPE, and PtoPSBB. Overexpression of PtoYAB11PSC serrated leaf margin, enlarged leaves, promoted photosynthesis and increased biomass. Overexpression of PsiYAB11 in P. tomentosa could rescue leaf margin serration and increase stomatal density and light damage repair ability. In poplar, YAB11-NGAL1is sensitive to environmental conditions and play positive regulator of leaf margin serration. It might be important regulator which bridge environment signaling to leaf morphological plasticity.
Protein 3D structure-based neural networks highly improve the accuracy in compound-protein binding affinity prediction

Theoretically, the accuracy of computational models in predicting compound-protein binding affinities (CPAs) could be improved by the introduction of protein 3D structure information. However, most of these models still suffer from a low accuracy due to the lack of an efficient approach to encode informative protein features. The major challenge is how to combine the multi-modal information such as the residue sequence of the protein, residue atom coordinates and the torsion angles. To tackle this problem, we develop F ast E volutional A ttention and T horoughgoing-graph N eural N etworks (FeatNN) to facilitate the application of protein 3D structure information for predicting CPAs. Specifically, we established a novel end-to-end architecture to jointly embed torsion matrix, discrete distance matrix, and sequence information of protein and extract compound features with deep graph convolution layers. In addition, a new pairwise mapping attention mechanism is introduced to comprehensively learn potential interaction information between proteins and compounds. FeatNN considerably outperforms various state-of-the-art baselines in CPA prediction with the Pearson value elevated by about 35.7%. Thus, FeatNN provides an outstanding method for highly accurate CPA prediction and facilitates high-throughput virtual screening of drug candidates.
High frequency spike inference with particle Gibbs sampling

Fluorescent calcium indicators are indispensable tools for monitoring the spiking activity of large neuronal populations in animal models. However, despite the plethora of algorithms developed over the last decades, accurate spike time inference methods for spike rates greater than 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms by analyzing the CASCADE benchmark datasets. The analysis of fluorescence transients recorded using an ultrafast genetically encoded calcium indicator, GCaMP8f, demonstrates the ability of our method to infer spike time intervals as short as five milliseconds. Overall, our study describes a Bayesian inference method to detect neuronal spiking patterns and their uncertainty. The use of particle Gibbs samplers allows for unbiased estimates of spike times and all model parameters, and it provides a flexible statistical framework to test more specific models of calcium indicators.
Functional plasticity and recurrent cell states of malignant B cells in follicular lymphoma

Follicular lymphoma (FL) derives from malignant transformation of germinal center (GC) B cells. FL malignant B cells are heterogeneous and diverge from their GC B cell-of-origin, but the diversity, function, and location of malignant B cell states remain to be addressed. Based on integrative single-cell RNA-seq, we identified and studied recurrent FL malignant B cell states and dynamics. Most FL B cells spanned a continuum of states from proliferating GC-like to quiescent memory (Mem)-like cell states. That GC-to-Mem axis was the main source of intra-tumor transcriptional heterogeneity. While FL B cell states were independent from subclonal B cell receptor genetics divergence, T follicular helper (TFH) cell-derived signals controlled the transition from Mem-like to GC-like states. GC-like, TFH-activated and Mem-like FL B cells tended to occupy distinct niches within and around tumor follicles. Our study characterizes novel malignant cell states recurrent in B cell lymphomas, and highlights the functional plasticity of malignant B cells.
The Effects of Single Strains and Mixtures of Probiotic Bacteria on Immune Profile in Liver, Spleen, and Peripheral Blood

Probiotic bacteria have potential use as immunomodulators but comparative data on their immunological effects are very limited. The aim of this study was to characterize the effect of oral administration of probiotic strains, alone or as mixtures, on systemic and organ-specific immune responses. For this purpose, healthy C57BL/6 mice were perorally administered probiotics for 3 weeks. A total of five common probiotic strains, Lactobacillus rhamnosus species GG (LGG) and LC705, Bifidobacterium breve 99 (Bb99), Propionibacterium freudenreichii Shermanii JS (PJS), and Escherichia coli Nissle 1917 (EcN), and two of their mixtures, were tested. Livers, spleens, and blood were collected for investigation. A number of five treatments increased the abundance of the natural killer (NK) cells. Bb99 had the most prominent effect on hepatic NK cells (20.0 ± 1.8%). LGG (liver: 5.8 ± 1.0%; spleen: 1.6 ± 0.4%), Bb99 (liver: 13.9 ± 4.3%; spleen: 10.3 ± 3.7%), and EcN (liver: 8.5 ± 3.2%; spleen: 1.0 ± 0.2%) increased the percentage of both the hepatic and splenic T-helper 17 cells. Moreover, LGG (85.5 ± 3.0%) and EcN (89.6 ± 1.2%) increased the percentage of splenic regulatory T-cells. The tested mixtures of the probiotics had different immunological effects from their individual components on cell-mediated responses and cytokine production. In conclusion, our results confirm that the immunomodulatory potential of the probiotics is strain- and organ/tissue-specific, and the effects of probiotic mixtures cannot be predicted based on their single constituents.
Bacillus cereus (EG-Q3) in the Gut of Ectropis grisescens Contributes to Host Response to Starvation Conditions

The gut bacteria of insects play an important role in their nutrition, maintenance, and ecological adaption. Ectropis grisescens is the most important leaf-feeding pest in tea gardens in China. In order to explore whether E. grisescens adaptation under starvation stress is related to its gut bacteria, we used a culture-independent method to compare the composition and diversity of their gut bacteria under starvation treatment. The results revealed no significant changes in core gut bacteria composition and diversity within 24 h of starvation. However, non-core gut bacterial Bacillus increased significantly under starvation conditions. B. cereus strain EG-Q3 isolated from the gut of E. grisescens in carbon source-selected medium showed the ability to degrade fat bodies from E. grisescens in vitro and in vivo. Moreover, the fat-lowering ratio of E. grisescens fed with B. cereus strain EG-Q3 (6.76 ± 1.281%) was significantly higher than that of the control group (3.96 ± 0.801%, t = 4.15, df = 8, p < 0.01) after starvation for 4 h. These findings suggest that non-core gut bacterial B. cereus strain EG-Q3 contributes to host adaptation to starvation. Together, this research provides evidence that E. grisescens may benefit from non-core gut bacteria under starvation conditions.
Establishment and Verification of Prognostic Nomograms for Young Women With Breast Cancer Bone Metastasis

Purpose The prognosis of patients with metastatic breast cancer usually varies greatly among individuals. At present, the application of nomogram is very popular in metastatic tumors. The present study was conducted to identify independent survival predictors and construct nomograms among young women with breast cancer bone metastasis (BCBM). Patients and Methods We searched the Surveillance, Epidemiology, and End Results (SEER) database to identify young women diagnosed with BCBM between 2010 and 2016. We first analyzed the potential risk factors of overall survival (OS) and cancer-specific survival (CSS) by applying univariate Cox regression analysis. Then we conducted multivariate Cox analysis to identify independent survival predictors. Based on significant independent predictors, we developed and validated novel prognostic nomograms by using the R version 4.1. 0 software. Results We finally identified 715 eligible young women with BCBM for survival analysis, of which 358 patients were in the training set, and 357 patients in the validation set. Approximately four-fifths of patients are between 31 and 40 years old. The 5-year OS and CSS rates of this research population were 41.9 and 43.3%, respectively. Multivariate analysis revealed seven independent predictors of both OS and CSS, including race, tumor subtype, tumor size, surgical treatment, brain metastasis, liver metastasis, and lung metastasis. Based on these predictors, we developed and validated OS and CSS nomograms. The C-index of the OS nomogram reached 0.728 and 0.73 in the training and validation sets, respectively. The C-index of the CSS nomogram reached 0.743 and 0.695 in the training and validation sets, respectively. Meanwhile, high quality calibration plots were revealed in both OS and CSS nomograms. Conclusion The current novel nomograms can provide an individualized survival evaluation of young women with BCBM and instruct clinicians to treat them appropriately.
Utility of Biology-Guided Radiotherapy to De Novo Metastases Diagnosed During Staging of High-Risk Biopsy-Proven Prostate Cancer

Background Biology-guided radiotherapy (BgRT) uses real-time functional imaging to guide radiation therapy treatment. Positron emission tomography (PET) tracers targeting prostate-specific membrane antigen (PSMA) are superior for prostate cancer detection than conventional imaging. This study aims at describing nodal and distant metastasis distribution from prostate cancer and at determining the proportion of metastatic lesions suitable for BgRT. Methods A single-institution patient subset from the ProPSMA trial (ID ACTRN12617000005358) was analysed. Gross tumour volumes (GTV) were delineated on the CT component of a PSMA PET/CT scan. To determine the suitability of BgRT tracking zones, the normalized SUV (nSUV) was calculated as the ratio of SUVmax inside the GTV to the SUVmean of adjacent three-dimensional shells of thickness 5 mm/10 mm/20 mm as a measure of signal to background contrast. Targets were suitable for BgRT if (1) nSUV was larger than an nSUV threshold and (2) non-tumour tissue inside adjacent shell was free of PET-avid uptake. Results Of this cohort of 84 patients, 24 had at least one pelvic node or metastatic site disease, 1 to 13 lesions per patient, with a total of 98 lesions (60 pelvic nodes/38 extra-pelvic nodal diseases and haematogenous metastases). Target volumes ranged from 0.08 to 9.6 cm3 while SUVmax ranged from 2.1 to 55.0. nSUV ranged from 1.9 to 15.7/2.4 to 25.7/2.5 to 34.5 for the 5 mm/10 mm/20 mm shell expansion. Furthermore, 74%/68%/34% of the lesions had nSUV ≥ 3 and were free of PSMA PET uptake inside the GTV outer shell margin expansion of 5 mm/10 mm/20 mm. Adjacent avid organs were another lesion, bladder, bowel, ureter, prostate, and liver. Conclusions The majority of PSMA PET/CT-defined radiotherapy targets would be suitable for BgRT by using a 10-mm tracking zone in prostate cancer. A subset of lesions had adjacent non-tumour uptake, mainly due to the proximity of ureter or bladder, and may require exclusion from emission tracking during BgRT.
Higher Peripheral Inflammation Is Associated With Lower Orbitofrontal Gamma Power in Chronic Tinnitus

Chronic tinnitus, the continuous perception of a phantom sound, is a highly prevalent audiological symptom, for which the underlying pathology has not yet been fully understood. It is associated with neurophysiological alterations in the central nervous system and chronic stress, which can be related with a disinhibition of the inflammatory system. We here investigated the association between resting-state oscillatory activity assessed with Magnetoencephalography (MEG), and peripheral inflammation assessed by C-reactive protein (CRP) in a group of patients with chronic tinnitus (N = 21, nine males, mean age: 40.6 ± 14.6 years). Additionally, CRP was assessed in an age- and sex-matched healthy control group (N = 21, nine males, mean age: 40.9 ± 15.2 years). No MEG data was available for the control group. We found a significant negative correlation between CRP and gamma power in the orbitofrontal cortex in tinnitus patients (p < 0.001), pointing to a deactivation of the orbitofrontal cortex when CRP was high. No significant clusters were found for other frequency bands. Moreover, CRP levels were significantly higher in the tinnitus group than in the healthy controls (p = 0.045). Our results can be interpreted based on findings from previous studies having disclosed the orbitofrontal cortex as part of the tinnitus distress network. We suggest that higher CRP levels and the associated deactivation of the orbitofrontal cortex in chronic tinnitus patients is maintaining the tinnitus percept through disinhibition of the auditory cortex and attentional or emotional top-down processes. Although the direction of the association (i.e., causation) between CRP levels and orbitofrontal gamma power in chronic tinnitus is not yet known, inflammation reducing interventions are promising candidates when developing treatments for tinnitus patients. Overall, our study highlights the importance of considering immune-brain communication in tinnitus research.
The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.
The Antioxidant, Anti-Inflammatory and Immunomodulatory Effects of Camel Milk

Camel milk (CM) has been found to have several health benefits, including antiviral, antibacterial, anti-tumor, anti-fungal, antioxidant, hypoglycaemic and anti-cancer activities. In addition, CM can counter signs of aging and may be a useful naturopathic treatment for autoimmune diseases. The composition of CM varies with geographic origin, feeding conditions, seasonal and physiological changes, genetics and camel health status. In the present review, we collate the diverse scientific literature studying antioxidant, anti-inflammatory and immunomodulatory effects of CM and its bioactive compounds. The databases Scopus, PubMed, and Web of Science were searched until the end of September 2021 using the keywords: camel milk, antioxidant, anti-inflammatory, immunomodulatory. The anti-inflammatory mechanism of CM in various inflammatory disorders was consistently reported to be through modulating inflammatory cells and mediators. The common anti-inflammatory bioactive components of CM seem to be lactoferrin. The antioxidant effects of α-lactalbumin, β-caseins and vitamin C of CM work by reducing or inhibiting the production of reactive oxygen species (ROS), hydroxyl radicals, nitric oxide (NO), superoxide anions and peroxyl radicals, likely alleviating oxidative stress. Higher levels of protective proteins such as lysozyme, IgG and secretory IgA compared to cow’s milk, and insulin-like protein activity of CM on ß cells appear to be responsible for the immunomodulatory properties of CM. The evidence indicates that CM and its bioactive components has the potential to be a therapeutic value for diseases that are caused by inflammation, oxidative stress and/or immune-dysregulation.
The Role of Syncytin in Placental Angiogenesis and Fetal Growth

Background: Syncytin, a retroviral envelope protein, is specifically expressed on trophoblast cells and mediates formation of the syncytiotrophoblast through fusogenic activity. Decreased expression of Syncytin was found in fetal growth restriction placentas. Results: By generating an inducible knockout of the syncytin-a gene in mice, we show a specific disruption of placental angiogenesis with abnormal formation of two syncytiotrophoblast layers. Consistent with the defects observed in vivo, conditioned medium collected from trophoblast cells, following Syncytin-1 knockdown, contains lower expression of vascular endothelial growth factor and placental growth factor, and higher levels of soluble fms-like protein kinase-1 in BeWo and HTR-8/SVneo cells which related with suppressed PI3K/Akt/mTOR pathway, and is reduced in ability to induce tube formation by HUVECs. Conclusion: Syncytin participates in angiogenesis during placental development was first identified both in vivo and in vitro. Here, we give a new sight on understanding syncytin and pathophysiology of placenta related disease such as fetal growth restriction.
Total Cerebral Small Vessel Disease Score and Cerebral Bleeding Risk in Patients With Acute Stroke Treated With Intravenous Thrombolysis

Objective The aim of this study was to investigate the association of total cerebral small vessel disease (cSVD) score with the risk of intracerebral hemorrhage (ICH) in patients with acute ischemic stroke who received intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA). Methods We retrospectively reviewed clinical data from two stroke registries of patients with acute ischemic stroke treated with IVT. We assessed the baseline magnetic resonance (MR) visible cSVD markers and total cSVD score (ranging from 0 to 4) between patients with and without ICH after IVT. Logistic regression analysis was used to determine the association of total cSVD score with the risk of ICH after IVT, adjusted for cofounders selected by least absolute shrinkage and selection operator (LASSO). We additionally performed an E-value analysis to fully explain away a specific exposure-outcome association. Receiver operating characteristic (ROC) curve analysis was used to quantify the predictive potential of the total cSVD score for any ICH after IVT. Results Among 271 eligible patients, 55 (20.3%) patients experienced any ICH, 16 (5.9%) patients experienced a symptomatic ICH (sICH), and 5 (1.85%) patients had remote intracranial parenchymal hemorrhage (rPH). Logistic regression analysis showed that the risk of any ICH increased with increasing cSVD score [per unit increase, adjusted odds ratio (OR) 2.03, 95% CI 1.22–3.41, P = 0.007]. Sensitivity analyses using E-value revealed that it would need moderately robust unobserved confounding to render the exposure-outcome (cSVD-any ICH) association null. ROC analysis showed that compared with the National Institutes of Health Stroke Scale (NIHSS) score alone, a combination of cSVD and NIHSS score had a larger area under the curve for any ICH (0.811, 95% CI 0.756–0.866 vs. 0.784, 95% CI 0.723–0.846, P = 0.0004). Conclusion The total cSVD score is associated with an increased risk of any ICH after IVT and improves prediction for any ICH compared with NIHSS alone.