Miracle-dz/UniFAR-FTUs huggingface dataset:
Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression

The parasite Toxoplasma gondii has a counterdefense system against interferon-γ (IFN-γ)-dependent host immunity which relies on the secretion of parasite effector proteins. ROP18 is one of the effector, which is released into host cells to inactivate IFN-γ-dependent anti-Toxoplasma host proteins. The mechanism by which Toxoplasma ROP18 subverts host immunity has been extensively analyzed, but how Toxoplasma produces this virulence factor remains unclear. ABSTRACT Toxoplasma gondii secretes various virulence effector molecules into host cells to disrupt host interferon-γ (IFN-γ)-dependent immunity. Among these effectors, ROP18 directly phosphorylates and inactivates IFN-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), leading to the subversion of IFN-inducible GTPase-induced cell-autonomous immunity. The modes of action of ROP18 have been studied extensively; however, little is known about the molecular mechanisms by which ROP18 is produced in the parasite itself. Here, we report the role of T. gondii transcription factor IWS1 in ROP18 mRNA expression in the parasite. Compared with wild-type virulent type I T. gondii, IWS1-deficient parasites showed dramatically increased loading of IRGs and GBPs onto the parasitophorous vacuole membrane (PVM). Moreover, IWS1-deficient parasites displayed decreased virulence in wild-type mice but retained normal virulence in mice lacking the IFN-γ receptor. Furthermore, IWS1-deficient parasites showed severely decreased ROP18 mRNA expression; however, tagged IWS1 did not directly bind with genomic regions of the ROP18 locus. Ectopic expression of ROP18 in IWS1-deficient parasites restored the decreased loading of effectors onto the PVM and in vivo virulence in wild-type mice. Taken together, these data demonstrate that T. gondii IWS1 indirectly regulates ROP18 mRNA expression to determine fitness in IFN-γ-activated host cells and mice. IMPORTANCE The parasite Toxoplasma gondii has a counterdefense system against interferon-γ (IFN-γ)-dependent host immunity which relies on the secretion of parasite effector proteins. ROP18 is one of the effector, which is released into host cells to inactivate IFN-γ-dependent anti-Toxoplasma host proteins. The mechanism by which Toxoplasma ROP18 subverts host immunity has been extensively analyzed, but how Toxoplasma produces this virulence factor remains unclear. Here, we show that Toxoplasma transcription factor IWS1 is important for ROP18 mRNA expression in the parasite. Loss of IWS1 from virulent Toxoplasma leads to dramatically decreased ROP18 mRNA expression, resulting in profoundly decreased virulence due to greater activity of IFN-γ-dependent host immune responses. Thus, Toxoplasma prepares the critical virulence factor ROP18 via an IWS1-dependent system to negate IFN-γ-dependent antiparasitic immunity and thus survive in the host.
Adverse events following the first, second and third doses of a COVID-19 vaccine in hemodialysis patients

Abstract Background This study aimed to identify adverse events following the first three doses of COVID-19 vaccines in hemodialysis (HD) patients. Risk factors associated with postvaccination adverse events were explored. Methods Postvaccination adverse events in 438 HD patients who received 3 doses of COVID-19 vaccines were prospectively assessed. The adverse events among three doses were compared using generalized linear mixed models. Factors associated with adverse events were assessed with multivariate analyses. Results The vast majority of participants received Oxford/AstraZeneca ChAdOx1 as their first two doses and Moderna mRNA-1273 as their third dose. Overall, 79%, 50% and 84% of the participants experienced at least one adverse event after their first, second, and third doses, respectively. These adverse events were mostly minor, short-lived and less than 5% reported daily activities being affected. Compared with the first dose, the second dose caused a lower rate of adverse events. Compared with the first dose, the third dose elicited a higher rate of injection site reactions and a lower rate of systemic reactions. Multivariate analyses showed that every 10-year increase of age (odds ratio 0.67, 95% confidence intervals 0.57-0.79) was associated with decreased risk of adverse events, while female sex (2.82, 1.90-4.18) and arteriovenous fistula (1.73, 1.05–2.84) were associated with increased risk of adverse events. Compared with Oxford/AstraZeneca ChAdOx1, Moderna mRNA-1273 was associated with an increased risk of injection site reactions. Conclusions COVID-19 vaccination was well tolerated in HD patients. Age, sex, dialysis vascular access and vaccine types were associated with postvaccination adverse events.
Heterogeneity in winged helix‐turn‐helix and substrate DNA interactions: Insights from theory and experiments

Specific interactions between transcription factors (TFs) and substrate DNA constitute the fundamental basis of gene expression. Unlike in TFs like basic helix‐loop‐helix or basic leucine zippers, prediction of substrate DNA is extremely challenging for helix‐turn‐helix (HTH). Experimental techniques like chromatin immunoprecipitation combined with massively parallel DNA sequencing remains a viable option. We characterize the molecular basis of heterogeneity in HTH‐DNA interaction using in silico tools and thence validate them experimentally. Given the profound functional diversity in HTH, we focus primarily on winged‐HTH (wHTH). We consider 180 wHTH TFs, whose experimental three‐dimensional structures are available in DNA bound/unbound conformations. Starting with PDB‐wide scanning and curation of data, we construct a phylogenetic tree, which distributes 180 wHTH sequences under multiple sub‐groups. Structure‐sequence alignment followed by detailed intra/intergroup analysis, covariation studies and extensive network theory analysis help us to gain deep insight into heterogeneous wHTH‐substrate DNA interactions. A central aim of this study is to find a consensus to predict the substrate DNA sequence for wHTH, amidst heterogeneity. The strength of our exhaustive theoretical investigations including molecular docking are successfully tested through experimental characterization of wHTH TF from Sulfurimonas denitrificans.
Detection of colon cancer recurrences during follow-up care by general practitioners vs surgeons

Abstract Background In the I CARE study, colon cancer patients were randomly assigned to receive follow-up care from either a general practitioner (GP) or a surgeon. Here, we address a secondary outcome, namely, detection of recurrences and effect on time to detection of transferring care from surgeon to GP. Methods Pattern, stage, and treatment of recurrences were described after 3 years. Time to event was defined as date of surgery, until date of recurrence or last follow-up, with death as competing event. Effects on time to recurrence and death were estimated as hazard ratios (HRs) using Cox regression. Restricted mean survival times were estimated. Results Of 303 patients, 141 were randomly assigned to the GP and 162 to the surgeon. Patients were male (67%) with a mean age of 68.0 (8.4) years. During follow-up, 46 recurrences were detected; 18 (13%) in the GP vs 28 (17%) in the surgeon group. Most recurrences were detected via abnormal follow-up tests (74%) and treated with curative intent (59%). Hazard ratio for recurrence was 0.75 (95% confidence interval [CI] = 0.41 to 1.36) in GP vs surgeon group. Patients in the GP group remained in the disease-free state slightly longer (2.76 vs 2.71 years). Of the patients, 38 died during follow-up; 15 (11%) in the GP vs 23 (14%) in the surgeon group. Of these, 21 (55%) deaths were related to colon cancer. There were no differences in overall deaths between the groups (HR = 0.76, 95% CI = 0.39 to 1.46). Conclusion Follow-up provided by GPs vs surgeons leads to similar detection of recurrences. Also, no differences in mortality were found.
Splicing factor SNRPA associated with microvascular invasion promotes hepatocellular carcinoma metastasis through activating NOTCH1/Snail pathway and is mediated by circSEC62/miR‐625‐5p axis

Microvascular invasion (MVI) is a crucial risk factor related to the metastasis of hepatocellular carcinoma (HCC), but the underlying mechanisms remain to be revealed. Characterizing the inherent mechanisms of MVI may aid in the development of effective treatment strategies to improve the prognosis of HCC patients with metastasis. Through the Gene Expression Omnibus (GEO) database, we identified that small nuclear ribonucleoprotein polypeptide A (SNRPA) was related to MVI in HCC. SNRPA was overexpressed in MVI‐HCC and correlated with poor patient survival. Mechanistically, SNRPA promoted the epithelial‐mesenchymal transition (EMT)‐like process for HCC cells to accelerate metastasis by activating the NOTCH1/Snail pathway in vitro and in vivo. Importantly, circSEC62 upregulated SNRPA expression in HCC cells via miR‐625‐5p sponging. Taking these results together, our study identified a novel regulatory mechanism among SNRPA, miR‐625‐5p, circSEC62 and the NOTCH1/Snail pathway in HCC, which promoted metastasis of HCC and may provide effective suggestions for improving the prognosis of HCC patients with metastasis.
A STEPWISE CONFIDENCE INTERVAL PROCEDURE BASED ON AN ASYMMETRIC LOSS FUNCTION WITH APPLICATIONS TO TOXICOLOGICAL EVALUATION

The purpose of toxicological studies is a safety assessment of compounds (e.g. pesticides, pharmaceuticals, industrial chemicals and food additives) at various dose levels. Because a mistaken declaration that a really non‐equivalent dose is equivalent could have dangerous consequences, it is important to adopt reliable statistical methods that can properly control the family‐wise error rate. We propose a new stepwise confidence interval procedure for toxicological evaluation based on an asymmetric loss function. The new procedure is shown to be reliable in the sense that the corresponding family‐wise error rate is well controlled at or below the pre‐specified nominal level. Our simulation results show that the new procedure is to be preferred over the classical confidence interval procedure and the stepwise procedure based on Welch's approximation in terms of practical equivalence/safety. The implementation and significance of the new procedure are illustrated with two real data sets: one from a reproductive toxicological study on Nitrofurazone in Swiss CD‐1 mice, and the other from a toxicological study on Aconiazide.
Next‐generation sequencing clarified why first‐line treatment with osimertinib was ineffective in an autopsied case of EGFR‐mutated lung squamous cell carcinoma

Epidermal growth factor receptor (EGFR)‐mutated squamous cell carcinoma (SCC) is less common than adenocarcinoma. The third‐generation EGFR‐tyrosine kinase inhibitor, osimertinib, is effective in EGFR‐mutated lung adenocarcinoma, but its efficacy in EGFR‐mutated lung SCC is unclear. The patient was an 83‐year‐old male. He was diagnosed with SCC of the lung, and molecular analysis revealed that the tumor was positive for EGFR exon19 deletion. He was treated with osimertinib 80 mg/day. No adverse events were observed, but after 18 days of therapy, he complained of dyspnea, and a computed tomography scan showed enlarged lung cancer. The case was categorized as a progressive disease. The patient died 3 weeks later. The autopsy findings confirmed the diagnosis of lung SCC, with morphology and immunohistochemical staining identical to the tumor obtained by bronchoscopy. Next‐generation sequencing showed the presence of TP53 R158L, CDK6, and KRAS amplifications. The current case report shows that next‐generation sequencing can explain why osimertinib is ineffective in EGFR‐mutated SCC.
Leptin-deficient ob/ob mice exhibit periodontitis phenotype and altered oral microbiome.

BACKGROUND AND OBJECTIVE Leptin-deficient obesity is associated with various systemic diseases including diabetes and low bone mass phenotype. However, the periodontal status of leptin-deficient obese individuals is still unclear. In this study, we aimed to analyze the periodontal status, alveolar bone phenotype, and oral microbiome status in leptin-deficient obese mice (ob/ob mice). METHODS This study used 12-week-old wild-type and ob/ob male mice. The alveolar bone phenotype and periodontal status in the maxilla were analyzed by micro-CT and histological analysis. Osteoclasts in alveolar bone were visualized by TRAP staining. Expressions of inflammatory markers (MMP-9, IL-1β, and TGF-β1) and osteoclastogenic markers (RANKL and OPG) in periodontium were analyzed by immunohistochemistry and RT-qPCR. The oral microbiome was analyzed by 16 S rDNA sequencing. RESULTS CEJ-ABC distance in maxillary molars (M1-M3) of ob/ob mice was significantly higher compared with that of wild-type. The alveolar bone BV/TV ratio was reduced in ob/ob mice compared with wild-type. Higher numbers of osteoclasts were observed in ob/ob mice alveolar bone adjacent to the molar root. Epithelial hyperplasia in gingiva and disordered periodontal ligaments was observed in ob/ob mice. RANKL/OPG expression ratio was increased in ob/ob mice compared with wild-type. Expressions of inflammatory markers MMP-9, IL-1β, and TGF-β1 were increased in ob/ob mice compared with wild-type. Oral microbiome analysis showed that beneficial bacteria Akkermansia and Ruminococcaceae_UCG_014 were more abundant in the wild-type mice while the inflammation-related Flavobacterium was more abundant in ob/ob mice. CONCLUSION In conclusion, ob/ob mice showed higher expressions of inflammatory factors, increased alveolar bone loss, lower abundance of the beneficial bacteria, and higher abundance of inflammatory bacteria in the oral cavity, suggesting leptin-deficient obesity as a risk factor for periodontitis development in ob/ob mice.
The middle infrared properties of OH megamaser host galaxies

We compiled all 119 OH maser galaxies (110 out of them are megamasers, i.e., L-OH > 10 L-circle dot) published so far and cross-identified these OH masers with the Wide-Field Infrared Survey Explorer (WISE) catalog, to investigate the middle infrared (MIR) properties of OH maser galaxies. The WISE magnitude data at the 3.4, 4.6, 12 and 22 mu m (W1 to W4) are collected for the OH maser sample and one control sample, which are non-detection sources. The color-color diagrams show that both OH megamaser (OHM) and non-OHM (ultra) luminous infrared galaxies ((U) LIRGs) are far away from the single blackbody model line and many of them can follow the path described by the power-law model. The active galaxy nuclei (AGN) fraction is about similar to 40% for both OHM and non-OHM (U) LIRGs, according to the AGN criteria W1-W2 >= 0.8. Among the Arecibo survey sample, OHM sources tend to have a lower luminosity at short MIR wavelengths (e. g., 3.4 mu m and 4.6 mu m) than that of non-OHM sources, which should come from the low OHM fraction among the survey sample with large 3.4 mu m and 4.6 mu m luminosity. The OHM fraction tends to increase with cooler MIR colors (larger F-22 (mu m)/F-3.4 (mu m)). These may be good for sample selection when searching OH megamasers, such as excluding extreme luminous sources at short MIR wavelengths, choosing sources with cooler MIR colors. In the case of the power-law model, we derived the spectral indices for our samples. For the Arecibo survey sample, OHM (U) LIRGs tend to have larger spectral index alpha(22-12) than non-OHM sources, which agrees with previous results. One significant correlation exists between the WISE infrared luminosity at 22 mu m and the color [W1]-[W4] for the Arecibo OHM hosts. These clues should provide suitable constraints on the sample selection for OH megamaser surveys by future advanced telescopes (e.g., FAST). In addition, the correlation of maser luminosity and the MIR luminosity of maser hosts tends to be non-significant, which may indirectly support the pumping of OHM emission that is dominated by the far infrared radiation, instead of the MIR radiation.
Innovative dual function nc-SiOx:H layer leading to a >16% efficient multi-junction thin-film silicon solar cell

We present our development of n-type nano-structured hydrogenated silicon oxide (nc-SiOx:H) as a dual-function layer in multi-junction solar cells. We optimized nc-SiOx:H and attained a conductivity suitable for a doped layer and optical property suitable for an inter-reflection layer. We tested the effectiveness of the dual-function nc-SiOx:H layer by replacing the normal n layer between the middle and the bottom cells in an a-Si:H/a-SiGe:H/nc-Si:H triple-junction structure. A significant gain in the middle cell current density of ∼1.0 mA/cm2 is achieved. We further optimized the component cells and the triple-junction structures and attained an initial active-area cell efficiency of 16.3%.
PorinPredict: In Silico Identification of OprD Loss from WGS Data for Improved Genotype-Phenotype Predictions of P. aeruginosa Carbapenem Resistance

Pseudomonas aeruginosa is a major cause of multidrug-resistant nosocomial infections. The emergence and spread of clones exhibiting resistance to carbapenems, a class of critical last-line antibiotics, is therefore closely monitored. ABSTRACT The increasing integration of genomics into routine clinical diagnostics requires reliable computational tools to identify determinants of antimicrobial resistance (AMR) from whole-genome sequencing data. Here, we developed PorinPredict, a bioinformatic tool that predicts defects of the Pseudomonas aeruginosa outer membrane porin OprD, which are strongly associated with reduced carbapenem susceptibility. PorinPredict relies on a database of intact OprD variants and reports inactivating mutations in the coding or promoter region. PorinPredict was validated against 987 carbapenemase-negative P. aeruginosa genomes, of which OprD loss was predicted for 454 out of 522 (87.0%) meropenem-nonsusceptible and 46 out of 465 (9.9%) meropenem-susceptible isolates. OprD loss was also found to be common among carbapenemase-producing isolates, resulting in even further increased MICs. Chromosomal mutations in quinolone resistance-determining regions and OprD loss commonly co-occurred, likely reflecting the restricted use of carbapenems for multidrug-resistant infections as recommended in antimicrobial stewardship programs. In combination with available AMR gene detection tools, PorinPredict provides a robust and standardized approach to link P. aeruginosa phenotypes to genotypes. IMPORTANCE Pseudomonas aeruginosa is a major cause of multidrug-resistant nosocomial infections. The emergence and spread of clones exhibiting resistance to carbapenems, a class of critical last-line antibiotics, is therefore closely monitored. Carbapenem resistance is frequently mediated by chromosomal mutations that lead to a defective outer membrane porin OprD. Here, we determined the genetic diversity of OprD variants across the P. aeruginosa population and developed PorinPredict, a bioinformatic tool that enables the prediction of OprD loss from whole-genome sequencing data. We show a high correlation between predicted OprD loss and meropenem nonsusceptibility irrespective of the presence of carbapenemases, which are a second widespread determinant of carbapenem resistance. Isolates with resistance determinants to other antibiotics were disproportionally affected by OprD loss, possibly due to an increased exposure to carbapenems. Integration of PorinPredict into genomic surveillance platforms will facilitate a better understanding of the clinical impact of OprD modifications and transmission dynamics of resistant clones.
Short-rise-time microwave pulse propagation through dispersive biological media

Numerical research is reported on the propagation of short microwave pulses into living, biological materials. These materials are dispersive, and data on the dielectric constant and conductivity for these materials follow a Debye model. A Fourier-series calculation is presented that predicts the occurrence of Brillouin precursors when the incident pulses have sufficiently short rise times. These transients are attenuated with increasing propagation distance but are attenuated more slowly than the carrier frequency of the pulse, which is attenuated exponentially with distance. An analysis of the numerical error resulting from truncation of the Fourier series is given. Upper-bound estimates of truncation error show good series convergence.
Temporal and spectral characteristics of terrestrial gamma flashes

We have analyzed the Burst and Transient Source Experiment (BATSE) high-resolution timing data for 13 terrestrial gamma flashes (TGFs) to better characterize this newly identified phenomenon, which may be related to atmospheric lightning. We find that the minimum timescale for TGF variability is ∼25–250 μs, with 50 μs near typical. In general, TGFs are spectrally much harder than cosmic gamma ray bursts (GRBs). We additionally find that as with GRBs, individual pulses within a TGF tend to peak earlier at higher energies. This time-asymmetry rules out models such as sweeping beams. We also find that different pulses can have different spectra, with spectra typically softening as a pulse progresses. Event-averaged spectra for the TGFs were examined and found to be better fit in the 25–500 keV range by a power law than by a blackbody model. However, in general, even a power law is not a perfect fit. We find correlation between minimum TGF timescale and the power law spectral index, with rapidly varying TGFs appearing softer. From empirical comparisons of timescales and structures we speculate that if TGFs are somehow related to known high-atmospheric lightning events, then they are more probably related to red sprites than to blue jets or transionospheric pulse pairs.
Radioactive iodine therapy decreases the recurrence of intermediate-risk PTC with low thyroglobulin levels.

PURPOSE This study conducted a propensity score matching (PSM) analysis to investigate whether radioactive iodine therapy (RAIT) is effective in reducing the recurrence of intermediate-risk papillary thyroid cancer (PTC) with low thyroglobulin (Tg) levels. METHODS In total, 1487 intermediate-risk PTC patients with unstimulated Tg ≤ 1 ng/mL or stimulated Tg ≤ 10 ng/mL after total thyroidectomy were enrolled retrospectively. The clinicopathological characteristics were compared between the non-RAIT and RAIT groups before and after PSM (1:4 matching). The impact of RAIT on biochemical recurrence and structural recurrence was evaluated. RESULTS Overall, 1349 (90.7%) patients underwent RAIT, and 138 (9.3%) did not. After a median follow-up time of 51 months, 30 patients presented with recurrence, including 11 structural and 19 biochemical recurrences. After PSM, compared to the RAIT group, the non-RAIT group had a higher rate of structural recurrence (5/138 vs. 5/552, P = 0.046) and biochemical recurrence (6/138 vs. 4/552, P = 0.005). Multivariate analysis showed that not receiving RAIT was an independent risk factor for structural recurrence (HR: 10.572, 95% CI: 2.439-45.843, P = 0.002) and biochemical recurrence (HR: 16.568, 95% CI: 3.670-74.803, P < 0.001). Kaplan-Meier analysis showed that non-RAIT group had more unfavorable RFS (structural and biochemical, all P < 0.05). CONCLUSIONS RAIT could decrease the recurrence risk of intermediate-risk PTC in patients with unstimulated Tg ≤ 1 ng/mL or stimulated Tg ≤ 10 ng/mL. Further prospective randomized studies are needed to confirm these findings.