Miracle-dz/UniFAR-FTUs huggingface dataset:
Transcription factor control of virulence in phytopathogenic fungi

Abstract Plant‐pathogenic fungi are a significant threat to economic and food security worldwide. Novel protection strategies are required and therefore it is critical we understand the mechanisms by which these pathogens cause disease. Virulence factors and pathogenicity genes have been identified, but in many cases their roles remain elusive. It is becoming increasingly clear that gene regulation is vital to enable plant infection and transcription factors play an essential role. Efforts to determine their regulatory functions in plant‐pathogenic fungi have expanded since the annotation of fungal genomes revealed the ubiquity of transcription factors from a broad range of families. This review establishes the significance of transcription factors as regulatory elements in plant‐pathogenic fungi and provides a systematic overview of those that have been functionally characterized. Detailed analysis is provided on regulators from well‐characterized families controlling various aspects of fungal metabolism, development, stress tolerance, and the production of virulence factors such as effectors and secondary metabolites. This covers conserved transcription factors with either specialized or nonspecialized roles, as well as recently identified regulators targeting key virulence pathways. Fundamental knowledge of transcription factor regulation in plant‐pathogenic fungi provides avenues to identify novel virulence factors and improve our understanding of the regulatory networks linked to pathogen evolution, while transcription factors can themselves be specifically targeted for disease control. Areas requiring further insight regarding the molecular mechanisms and/or specific classes of transcription factors are identified, and direction for future investigation is presented.
The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains

Sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins and is a well-established drug target. However, signaling functions of S1R in cells are poorly understood. Here, we test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER membrane. By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness and that increased local cholesterol concentration and/or membrane thickness in these microdomains can modulate signaling of inositol-requiring enzyme 1α in the ER. Further, S1R agonists cause disruption of S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains. Our results provide novel insights into S1R-mediated signaling mechanisms in cells.
Toxicity of quantum dots on target organs and immune system

Quantum dots (QDs), due to their superior luminous properties, have been proven to be a very promising biological probe, which can be used as a candidate material for clinical applications. The toxicity of QDs in the environment and biological systems has caused widespread concern in the nanosphere, but their immune toxicity and their impact on the immune system are still relatively unknown. At present, the research on the toxicity of QDs is mainly focused on in vitro models, but few have systematically evaluated their adverse effects on target organs. Animal studies have shown that QDs can be accumulated in various organs due to their main exposure routes, thereby posing a potential threat to major organs. This review briefly describes general characteristics and the wide medical applications of QDs and focuses on the adverse effects of QDs on major target organs, such as liver, lung, kidney, brain, and spleen, after acute and chronic exposure. QDs mainly cause changes in the corresponding indicators of target organs, such as oxidative damage, and in severe cases cause hyperemia, tissue necrosis, and even death. In addition to causing direct damage to target organs, QDs can also cause a large number of immune cells to accumulate and cause inflammatory reactions when causing damage to other major organs. Whether it is to avoid the risk of people contacting QDs in production and life, or to realize the clinical applications of QDs, is very essential to conduct systematic in vivo toxicity assessment of QDs.
Preliminary Comparison of Subcortical Structures in Elderly Subclinical Depression: Structural Analysis with 3T MRI

Depression in the elderly population has shown increased likelihood of neurological disorders due to structural changes in the subcortical area. However, further investigation into depression related subcortical changes is needed due to mismatches in structural analysis results between studies as well as scarcities in research regarding subcortical connectivity patterns of subclinical depression populations. This study aims to investigate structural differences in subcortical regions of aged participants with subclinical depression using 3Tesla MRI. In structural analysis, volumes of each subcortical region were measured to observe the volumetric difference and asymmetry between groups, but no significant difference was found. In addition, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) did not show any significant differences between groups. Structural analysis using probabilistic tractography indicated that the connection strength between left nucleus accumbens-right hippocampus, and right thalamus-right caudate was higher in the control group than the subclinical depression group. The differences in subcortical connection strength of subclinical depression groups, have shown to correlate with emotional and cognitive disorders, such as anxiety and memory impairment. We believe that the analysis of structural differences and cross-regional network measures in subcortical structures can help identify neurophysiological changes occurring in subclinical depression.
Investigation of product derived lymphoma following infusion of piggyBac modified CD19 chimeric antigen receptor T-cells.

We performed a Phase I clinical trial of donor derived CD19-specific chimeric antigen receptor T-cells (CAR T-cells) for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene capacity limitations of traditional viral vectors, CAR T-cells were produced using the piggyBac transposon system of genetic modification. Following CAR T-cell infusion, one patient developed a gradually enlarging retroperitoneal tumor due to a CAR expressing CD4+ T-cell lymphoma. Screening of other patients led to the detection of a second CAR T-cell tumor in thoracic para-aortic lymph nodes in an asymptomatic patient. Analysis of the first lymphoma showed a high transgene copy number, but no insertion into typical oncogenes. There were also structural changes such as altered genomic copy number and point mutations unrelated to the insertion sites. Transcriptome analysis showed transgene promoter driven upregulation of transcription of surrounding regions despite insulator sequences surrounding the transgene. However, marked global changes in transcription predominantly correlated with gene copy number rather than insertion sites. In both patients, the CAR T-cell derived lymphoma progressed and one patient died. We describe the first two cases of malignant lymphoma derived from CAR gene modified T-cells. Although CAR T-cells have an enviable record of safety to date, our results emphasize the need for caution and regular follow up of CAR T recipients, especially when novel methods of gene transfer are used to create genetically modified immune therapies. The trial was registered at www.anzctr. org.au as ACTRN12617001579381.
Distinct Features of Brain-Resident Macrophages: Microglia and Non-Parenchymal Brain Macrophages

Tissue-resident macrophages play an important role in maintaining tissue homeostasis and innate immune defense against invading microbial pathogens. Brain-resident macrophages can be classified into microglia in the brain parenchyma and non-parenchymal brain macrophages, also known as central nervous system-associated or border-associated macrophages, in the brain-circulation interface. Microglia and non-parenchymal brain macrophages, including meningeal, perivascular, and choroid plexus macrophages, are mostly produced during embryonic development, and maintained their population by self-renewal. Microglia have gained much attention for their dual roles in the maintenance of brain homeostasis and the induction of neuroinflammation. In particular, diverse phenotypes of microglia have been increasingly identified under pathological conditions. Single-cell phenotypic analysis revealed that microglia are highly heterogenous and plastic, thus it is difficult to define the status of microglia as M1/M2 or resting/activated state due to complex nature of microglia. Meanwhile, physiological function of non-parenchymal brain macrophages remain to be fully demonstrated. In this review, we have summarized the origin and signatures of brain-resident macrophages and discussed the unique features of microglia, particularly, their phenotypic polarization, diversity of subtypes, and inflammasome responses related to neurodegenerative diseases.
Aquatic microbial community is partially functionally redundant: insights from an in situ reciprocal transplant experiment

Microbial communities are considered to be functionally redundant, but few studies have tested this hypothesis empirically. In this study, we performed an in situ reciprocal transplant experiment on the surface and bottom waters of two lakes with disparate trophic states and tracked changes in their microbial community and functional attributes for 6 weeks using high-throughput sequencing and functional approaches. The communities from both lakes were resistant to changes in composition after the reciprocal transplant, but their functions tended to become similar to the incubating lakes’ functional profiles. A significant linear positive relationship was observed between the microbial community and functional attributes, though with varying scales of similarity, suggesting partial functional redundancy. Furthermore, the entropy-based L-divergence measure quantified the scale of partial functional redundancy in the lakes’ surface and bottom waters. This study establishes and quantifies the scale of partial functional redundancy in the freshwater ecosystem through empirical investigation.
Molecular genetics with clinical characteristics of Leber congenital amaurosis in the Han population of western China

ABSTRACT Purpose: Leber congenital amaurosis (LCA) is one of the earliest inherited retinal dystrophies (IRD) that leads to blindness. To date, there have been 25 LCA-associated genes reported in China as well as other countries. The current study aimed to present the dominant molecular genetics and clinical features of LCA in the Han population of western China. Methods: Our study comprised 37 patients with strictly defined Leber congenital amaurosis in a cohort of IRD (2009–2019). The mutations were detected by targeted next-generation sequencing (NGS), Sanger sequencing, and segregation analysis. The patients underwent comprehensive clinical examinations, analysis of phenotypes and genotypes. Results: Out of the 37 patients, 34 harbored known LCA genes; the detection rate of mutations was 91.9%. Forty-seven different alleles incorporated 21 novel mutations; 8 were known LCA-associated genes. The three most frequently mutated genes included CRB1 (27.0%), RDH12 (24.3%), and RPGRIP1 (18.9%). The CRB1-associated LCA showed a pigmented fundus; the RDH12-associated LCA featured macular atrophy. Our results revealed that CRB1 and RPGRIP1 genes occupied a greater proportion in the western Chinese population. The proportion of these two genes was similar in other regions of China as well. The difference existed in a larger proportion of RDH12-associated LCA in the western Chinese population. Conclusions: The new findings in our study group polished the spectrum of the novel mutations and phenotypes of LCA with regional and ethnic variations. This comprehensive database can provide essential information for gene therapies.
Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction

Objective Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties. Methods In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase–DNA (MPO–DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1–3). Results Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO–DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population. Conclusions In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.
The effect of cocoa-rich products on depression, anxiety, and mood: A systematic review and meta-analysis

Abstract In the popular imaginary, cocoa-derived products, like chocolate, represent a panacea for mood and affectivity. However, whether this is a myth or a fact has yet to be clarified. A systematic review and meta-analysis were conducted according to the PRISMA guidelines to investigate the effect of cocoa-derived food on depressive and anxiety symptoms, positive and negative affect. We searched Web of KnowledgeTM and PsycINFO up to April 3, 2020. After screening 761 records, we selected nine studies. Two trials evaluated the long-term effects of cocoa consumption (>1 week), two studies the short-term effects (3 days), while five studies were conducted in acute (single administration). Random-effects meta-analyses found an overall significant effect of cocoa-rich products on depressive (Hedge’s g = −0.42, 95% CI −0.67 to −0.17) and anxiety symptoms (Hedge’s g = −0.49, 95% CI −0.78 to −0.19). Moreover, both positive (Hedge’s g = 0.41, 95% CI 0.06 to 0.77) and negative affect (Hedge’s g = −0.47, 95% CI −0.91 to −0.03) significantly improved. In all meta-analyses, the effect size was medium, while heterogeneity was low. Our findings suggest that the consumption of cocoa-rich products may improve affect and mood in the short term. However, given the short duration of trials, our results cannot be generalized to long-term intake of cocoa-derived food. Cautious interpretation is also needed due to the low number of participants and studies included in the meta-analyses.
Ventilation Assessment by Carbon Dioxide Levels in Dental Treatment Rooms

It is important for dental care professionals to reliably assess carbon dioxide (CO2) levels and ventilation rates in their offices in the era of frequent infectious disease pandemics. This study was to evaluate CO2 levels in dental operatories and determine the accuracy of using CO2 levels to assess ventilation rate in dental clinics. Mechanical ventilation rate in air change per hour (ACHVENT) was measured with an air velocity sensor and airflow balancing hood. CO2 levels were measured in these rooms to analyze factors that contributed to CO2 accumulation. Ventilation rates were estimated using natural steady-state CO2 levels during dental treatments and experimental CO2 concentration decays by dry ice or mixing baking soda and vinegar. We compared the differences and assessed the correlations between ACHVENT and ventilation rates estimated by the steady-state CO2 model with low (0.3 L/min, ACHSS30) or high (0.46 L/min, ACHSS46) CO2 generation rates, by CO2 decay constants using dry ice (ACHDI) or baking soda (ACHBV), and by time needed to remove 63% of excess CO2 generated by dry ice (ACHDI63%) or baking soda (ACHBV63%). We found that ACHVENT varied from 3.9 to 35.0 in dental operatories. CO2 accumulation occurred in rooms with low ventilation (ACHVENT ≤6) and overcrowding but not in those with higher ventilation. ACHSS30 and ACHSS46 correlated well with ACHVENT (r = 0.83, P = 0.003), but ACHSS30 was more accurate for rooms with low ACHVENT. Ventilation rates could be reliably estimated using CO2 released from dry ice or baking soda. ACHVENT was highly correlated with ACHDI (r = 0.99), ACHBV (r = 0.98), ACHDI63% (r = 0.98), and ACHBV63% (r = 0.98). There were no statistically significant differences between ACHVENT and ACHDI63% or ACHBV63%. We conclude that ventilation rates could be conveniently and accurately assessed by observing the changes in CO2 levels after a simple mixing of household baking soda and vinegar in dental settings.
Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

Background This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers. Methods Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel. Results Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05). Conclusions The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
Association between Aortic Valve Calcification Progression and Coronary Atherosclerotic Plaque Volume Progression in the PARADIGM Registry.

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized β = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (β = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (β = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (β = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (β = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (β = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.
Two alternative methods for the retrieval of somatic cell populations from the mouse ovary

Abstract Many modern techniques employed to uncover the molecular fundamentals underlying biological processes require dissociated cells as their starting point/substrate. Investigations into ovarian endocrinology or folliculogenesis, therefore, necessitate robust protocols for dissociating the ovary into its constituent cell populations. While in the mouse, methods to obtain individual, mature follicles are well-established, the separation and isolation of single cells of all types from early mouse follicles, including somatic cells, has been more challenging. Herein we present two methods for the isolation of somatic cells in the ovary. These methods are suitable for a range of applications relating to the study of folliculogenesis and mouse ovarian development. First, an enzymatic dissociation utilising collagenase and a temporary, primary cell culture step using neonatal mouse ovaries which yields large quantities of granulosa cells from primordial, activating, and primary follicles. Second, a rapid papain dissociation resulting in a high viability single cell suspension of ovarian somatic cells in less than an hour, which can be applied from embryonic to adult ovarian samples. Collectively these protocols can be applied to a broad array of investigations with unique advantages and benefits pertaining to both.