Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome

Interferon Regulatory Factor 6 (IRF6) gene encodes a member of the IRF family of transcription factors. Mutations in IRF6 cause Van der Woude Syndrome (VWS), which is the most common malformation of syndromic orofacial clefts in humans.
Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib. Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10–78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. Significance: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.
Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

Structure-based stabilization of protein–protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.
Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment

Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70–80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic–pituitary–gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.
Single-Pulse TMS over the Parietal Cortex Does Not Impair Sensorimotor Perturbation-Induced Changes in Motor Commands

Abstract Intermittent exposure to a sensorimotor perturbation, such as a visuomotor rotation, is known to cause a directional bias on the subsequent movement that opposes the previously experienced perturbation. To date, it is unclear whether the parietal cortex is causally involved in this postperturbation movement bias. In a recent electroencephalogram study, Savoie et al. (2018) observed increased parietal activity in response to an intermittent visuomotor perturbation, raising the possibility that the parietal cortex could subserve this change in motor behavior. The goal of the present study was to causally test this hypothesis. Human participants (N = 28) reached toward one of two visual targets located on either side of a fixation point, while being pseudorandomly submitted to a visuomotor rotation. On half of all rotation trials, single-pulse transcranial magnetic stimulation (TMS) was applied over the right (N = 14) or left (N = 14) parietal cortex 150 ms after visual feedback provision. To determine whether TMS influenced the postperturbation bias, reach direction was compared on trials that followed rotation with (RS + 1) and without (R + 1) TMS. It was hypothesized that interfering with parietal activity would reduce the movement bias following rotated trials. Results revealed a significant and robust postrotation directional bias compared with both rotation and null rotation trials. Contrary to our hypothesis, however, neither left nor right parietal stimulation significantly impacted the postrotation bias. These data suggest that the parietal areas targeted here may not be critical for perturbation-induced motor output changes to emerge.
A Lifespan fMRI Study of Neurodevelopment Associated with Reading Chinese

Abstract We used functional magnetic resonance imaging (fMRI) to map the neural systems involved in reading Chinese in 125 participants 6–74 years old to examine two theoretical issues: how brain structure and function are related in the context of the lifetime neural development of human cognition and whether the neural network for reading is universal or different across languages. Our findings showed that a common network of left frontal and occipital regions typically involved in reading Chinese was recruited across all participants. Crucially, activation in left mid-inferior frontal regions, fusiform and striate–extrastriate sites, premotor cortex, right inferior frontal gyrus, bilateral insula, and supplementary motor area all showed linearly decreasing changes with age. These findings differ from previous findings on alphabetic reading development and suggest that early readers at age 6–7 are already using the same cortical network to process printed words as adults, though the connections among these regions are modulated by reading proficiency, and cortical regions for reading are tuned by experience toward reduced and more focused activation. This fMRI study has demonstrated, for the first time, the neurodevelopment of reading across the lifespan and suggests that learning experience, instead of pre-existing brain structures, determines reading acquisition.
Dynamics and Endocytosis of Flot1 in Arabidopsis Require CPI1 Function

Membrane microdomains are nano-scale domains (10–200 nm) enriched in sterols and sphingolipids. They have many important biological functions, including vesicle transport, endocytosis, and pathogen invasion. A previous study reported that the membrane microdomain-associated protein Flotillin1 (Flot1) was involved in plant development in Arabidopsis thaliana; however, whether sterols affect the plant immunity conveyed by Flot1 is unknown. Here, we showed that the root length in sterol-deficient cyclopropylsterol isomerase 1 (cpi1-1) mutants expressing Flot1 was significantly shorter than in control seedlings. The cotyledon epidermal cells in cpi1-1 mutants expressing Flot1 were smaller than in controls. Moreover, variable-angle total internal reflection fluorescence microscopy (VA-TIRFM) and single-particle tracking (SPT) analysis demonstrated that the long-distance Flot1-GFP movement was decreased significantly in cpi1-1 mutants compared with the control seedlings. Meanwhile, the value of the diffusion coefficient Ĝ was dramatically decreased in cpi1-1 mutants after flagelin22 (flg22) treatment compared with the control seedlings, indicating that sterols affect the lateral mobility of Flot1-GFP within the plasma membrane. Importantly, using confocal microscopy, we determined that the endocytosis of Flot1-GFP was decreased in cpi1-1 mutants, which was confirmed by fluorescence cross spectroscopy (FCS) analysis. Hence, these results demonstrate that sterol composition plays a critical role in the plant defense responses of Flot1.
Neuro-Ophthalmic Injuries With Systemic Neurologic Injury or Traumatic Brain Injury in Operation Iraqi Freedom and Operation Enduring Freedom.

BACKGROUND To analyze the final visual acuity (VA) of neuro-ophthalmologic injuries (NOI) in combat ocular trauma and to study the association of NOI with systemic neurologic injury (SNI) and traumatic brain injury (TBI). METHODS The Walter Reed Ocular Trauma Database was reviewed. Inclusion criteria were any US service member and Department of Defense civilians who suffered NOI, SNI, or TBI in Operation Iraqi Freedom or Operation Enduring Freedom. The primary outcome measure was the rate of poor final VA in patients with an NOI with secondary outcome measures the rate of SNI and TBI. in patients with NOI. RESULTS One hundred seventy-eight (20.00%) of 890 eyes had an NOI. Optic nerve injury was observed in 79 (44.38%) eyes, other cranial nerve injury in 68 (38.20%), Horner syndrome in 4 (2.25%), diplopia in 45 (25.28%), and ptosis in 13 (7.30%). In patients with NOI, 76 (42.69%) eyes had a final VA less than 20/200. In injured eyes (n = 359) of patients (n = 251) with TBI, 154 eyes (34.26%) had a final VA less than 20/200. In multivariate analysis, optic nerve injury (P < 0.001), unlike TBI (P = 0.47), was associated with final VA less than 20/200. SNI (n = 229) had a statistically significant association (odds ratio 29.8, 95% confidence interval 19.2-47.8, P < 0.001) with NOI. Optic nerve injury and cranial nerve injury were associated with TBI and SNI (all, P < 0.001). CONCLUSION Optic nerve injury and cranial nerve injury are associated with TBI and SNI. Optic nerve injury, but not TBI or cranial nerve injury, is associated with a poor final VA.
Neurochemical, behavioral, and neurogenic validation of a hyposerotonergic animal model by voluntary oral consumption of PCPA.

The inhibitor of tryptophan hydroxylase, para-Chlorophenylalanine (PCPA), has been classically employed as a pharmacological tool to deplete serotonin (5-HT) in animal models and to evaluate whether this neurotransmitter is involved in the action of pharmacological compounds. PCPA is usually administrated by intraperitoneal (i.p.) injections, which are stressful and painful. To avoid i.p. injections, we designed and validated a protocol for PCPA oral administration. C57Bl/6 elite male mice received PCPA during 7 days either i.p. or by giving the drug inside jelly cubes at an estimated dose of 500 mg/kg on days 1 and 2, and 250 mg/kg for the rest of the treatment. 5-HT levels decreased by 85%, and 55% in the hippocampus of mice treated with oral or i.p PCPA respectively, whereas in the prefrontal cortex, 5-HT levels decreased by 65% (oral), and 50% (i.p.). Behavioral tests, like the Forced Swimming test (FST), the Nestlet Shredding test (NST), and the Marble Burying test (MBT) were performed. In the FST, mice received fluoxetine i.p. 30 min before the test. In mice with oral PCPA-treatment, Fluoxetine did not induce significant reductions of immobility, indicating that reduction of 5-HT levels was effective. No effect of i.p. or oral 5-HT depletion was observed in the NST nor in the MBT. In a second experiment, mice received oral PCPA for 8 weeks: again, serotonin levels were significantly decreased in both hippocampus and cortex, and effects on hippocampal neurogenesis replicated previous observations in hyposerotonergic mice. Therefore, neurochemical, behavioral, and neurogenic results allow us to validate this refined protocol for voluntary oral consumption of PCPA.
Addressing Gaps Between Payer Policies and AASM Clinical Practice Guidelines Using Scorecards.

None The AASM Payer Policy Review Committee (PPRC) launched an initiative to assess the alignment between clinical practice guidelines (CPGs) and private payer medical policies. This article summarizes the importance of the initiative, details the scorecard development process, including an analysis of policy scores and subsequent revisions, and discusses the impact of the scorecards particularly as related to the scorecards on the CPG for diagnosis of obstructive sleep apnea (OSA) in adults. This initiative has increased communication and engagement amongst members of the PPRC and private payers, creating opportunities to advocate on behalf of sleep medicine providers and patients with sleep disorders, encouraging payers to modify existing policies so that evidence-based care is provided to patients with sleep disorders.
Magnetic resonance radiomics for prediction of extraprostatic extension in non-favorable intermediate- and high-risk prostate cancer patients

Background To investigate whether magnetic resonance (MR) radiomic features combined with machine learning may aid in predicting extraprostatic extension (EPE) in high- and non-favorable intermediate-risk patients with prostate cancer. Purpose To investigate the diagnostic performance of radiomics to detect EPE. Material and Methods MR radiomic features were extracted from 228 patients, of whom 86 were diagnosed with EPE, using prostate and lesion segmentations. Prediction models were built using Random Forest. Further, EPE was also predicted using a clinical nomogram and routine radiological interpretation and diagnostic performance was assessed for individual and combined models. Results The MR radiomic model with features extracted from the manually delineated lesions performed best among the radiomic models with an area under the curve (AUC) of 0.74. Radiology interpretation yielded an AUC of 0.75 and the clinical nomogram (MSKCC) an AUC of 0.67. A combination of the three prediction models gave the highest AUC of 0.79. Conclusion Radiomic analysis combined with radiology interpretation aid the MSKCC nomogram in predicting EPE in high- and non-favorable intermediate-risk patients.
Glucocorticoids affect metabolic but not muscle microvascular insulin sensitivity following high versus low salt intake.

Background Salt-sensitive hypertension is often accompanied by insulin resistance in obese individuals, but the underlying mechanisms are obscure. Microvascular function is known to affect both salt-sensitivity of blood pressure and metabolic insulin sensitivity. We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR). Methods In 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24h ABPM), insulin-mediated whole body glucose disposal (M/I-value; hyperinsulinemic, euglycemic clamp technique), IMMR (contrast enhanced ultrasound), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low and high salt diet during seven days in a randomized double-blind cross-over design.Results On a low, as compared to a high salt intake, MAP was lower, M/I-value was lower and IMMR was greater in both lean and abdominally obese individuals. In addition, Ln IMMR was inversely associated with MAP in lean participants on a low salt diet only. On a high salt diet, free water clearance decreased, and excretion of glucocorticoids and of amino acids involved in the urea cycle increased.Conclusion Our findings imply that hemodynamic and metabolic changes resulting from alterations in salt intake are not necessarily associated. Moreover, they are consistent with the concept that a high salt intake increases muscle glucose uptake as a response to high-salt-induced, glucocorticoid-drive muscle catabolism to stimulate urea production and thereby renal water conservation.Clinical Trial Registration Number: NCT02068781.
Functions of Vertebrate Ferlins

Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in DYSF (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in MYOF (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in OTOF (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development.
Effect of JAK-STAT pathway in regulation of fatty liver hemorrhagic syndrome in chickens

Objective To explore the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) in laying hens, an experiment was conducted to reveal the differences in histopathological observation and gene expression between FLHS group and normal group. Methods We compared the histopathological difference using hematoxylin and eosin staining and proceeded with RNA sequencing of adipose tissue to search differentially expressed genes and enriched biological processes and pathways. Then we validated the mRNA expression levels by real-time polymerase chain reaction and quantified protein levels in the circulation by enzyme-linked immunosorbent assay. Results We identified 100 differentially expressed transcripts corresponding to 66 genes (DEGs) were identified between FLHS-affected group and normal group. Seven DEGs were significantly enriched in the immune response process and lipid metabolic process, including phospholipase A2 group V, WAP kunitz and netrin domain containing 2, delta 4-desaturase sphingolipid 2, perilipin 3, interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), and suppressor of cytokine signaling 3 (SOCS3). And these genes could be the targets of immune response and be involved in metabolic homeostasis during the process of FLHS in laying hens. Based on functional categories of the DEGs, we further proposed a model to explain the etiology and pathogenesis of FLHS. IL-6 and SOCS3 mediate inflammatory responses and the satiety hormone of leptin, induce dysfunction of Jak-STAT signaling pathway, leading to insulin resistance and lipid metabolic disorders. Conversely, CNTF may reduce tissue destruction during inflammatory attacks and confer protection from inflammation-induced insulin resistance in FLHS chickens. Conclusion These findings highlight the therapeutic implications of targeting the JAK-STAT pathway. Inhibition of IL6 and SOCS3 and facilitation of CNTF could serve as a favorable strategy to enhance insulin action and improve glucose homoeostasis, which are of importance for treating obesity-related disorders for chickens.
Can Three‐Dimensional Visualization Technologies be More Effective than Cadavers for Dental Anatomy Education?

It was our pleasure to read the article by Lone et al. (2019), who developed and assessed a three-dimensional (3D) application for dental anatomy education. The authors concluded that the application was of equivalent educational value with extracted teeth, while they stated that computer-based 3D models enhance teaching outcomes. Relevant literature was cited at the introduction of the article, in order to support the authors' point of view (Mitov et al., 2010; Wright and Hendricson, 2010).
Surgical Choice for Different Types of Gallbladder Adenomyomatosis: An Initial Experience of 20 Years Laparoscopic Cholecystectomy

Objectives: The objective of this study was to compare the difference of clinical biochemical statistics in different types of gallbladder adenomyomatosis (GA). To investigate the different effects of patients between the 3 different types of GA. Materials and Methods: Retrospective analysis of the clinical data of the adenomyomatosis patients that come from our hospital between 2010 to 2018. According to the preoperative image (all cases are performed as elective surgery), it could be divided into 3 groups: group A: fundal (localized) type; group B: segmental type; group C: diffuse type. The number of each group is 136, 27, 17. We analyze the biochemical statistics (total bilirubin, direct bilirubin, serum bile acid, alanine aminotransferase, aspartate aminotransferase, cholinesterase, etc.) of the 3 groups to explore the difference in operative mode, operative time and prognosis between these 3 groups. Results: (1) In the liver function statistics, aspartate aminotransferase has the statistical significance (F=4.974, P=0.012); (2) And the diffuse adenomyomatosis might have a higher bile acid (F=6.048, P=0.005); (3) The segmental and diffuse adenomyomatosis is easier to be combined with stones (F=19.226, P<0.001); (4) The fundal adenomyomatosis seems to have a better prognosis: fewer hospital stay (F=4.519, P=0.018), fewer drainage time (F=6.575, P=0.004) and fewer complications (χ2=29.429, P<0.001). Conclusions: GA is a disease characterized by epithelial proliferation and hypertrophy of the muscles of the gallbladder wall with an outpouching of the mucosa into or through the thickened muscular layer and cannot be regarded as a precancerous lesion based on available evidence. As for asymptomatic GA, conservative treatment is recommended with ultrasound examinations twice a year. The fundal type GA can be treated by partial laparoscopic cholecystectomy. The segmental and diffuse-type should undergo a total laparoscopic cholecystectomy.
A novel assay for studying the involvement of blood cells in whole blood thrombin generation

Fluorogenic thrombin generation (TG) assays are commonly used to determine global coagulation phenotype in plasma. Whole blood (WB)‐TG assays reach one step closer to physiology by involving the intrinsic blood cells, but erythrocytes cause variable quenching of the fluorescence signals, hampering its routine application.