Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome

U7 snRNP is a multisubunit endonuclease required for 3′ end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, U7 snRNP lacks the Sm subunits D1 and D2 and instead contains two related proteins, Lsm10 and Lsm11. The remaining five subunits of the U7 heptameric Sm ring, SmE, F, G, B, and D3, are shared with the spliceosomal snRNPs. The pathway that assembles the unique ring of U7 snRNP is unknown. Here, we show that a heterodimer of Lsm10 and Lsm11 tightly interacts with the methylosome, a complex of the arginine methyltransferase PRMT5, MEP50, and pICln known to methylate arginines in the carboxy-terminal regions of the Sm proteins B, D1, and D3 during the spliceosomal Sm ring assembly. Both biochemical and cryo-EM structural studies demonstrate that the interaction is mediated by PRMT5, which binds and methylates two arginine residues in the amino-terminal region of Lsm11. Surprisingly, PRMT5 also methylates an amino-terminal arginine in SmE, a subunit that does not undergo this type of modification during the biogenesis of the spliceosomal snRNPs. An intriguing possibility is that the unique methylation pattern of Lsm11 and SmE plays a vital role in the assembly of the U7 snRNP.
Predictive value and accuracy of prenatal four-dimensional color ultrasound for fetal abnormal development

To investigate the value and accuracy of prenatal GE-E10 ultrasound Equipment in predicting fetal abnormal development. 160 pregnant women and women who received prenatal ultrasound examination were selected. Before delivery, all pregnant women were examined by conventional two-dimensional and four-dimensional (4D) ultrasound. 18 fetuses with abnormal development were detected by gold standard in 160 pregnant women. Sensitivity and specificity of two-dimensional color ultrasound in diagnosing fetal abnormal development were 78.38% and 82.60%. The sensitivity and specificity of 4D color ultrasound in diagnosing fetal abnormal development were 81.15% and 83.43%. ROC showed that the AUC (0.873) of 4D color ultrasound was higher than that of two-dimensional color ultrasound (0.827). The diagnostic efficiency of 4D ultrasound is greater. The accuracy, specificity and sensitivity of 4D color ultrasound in the diagnosis of fetal abnormal development is high, and it is valuable for prenatal screening of macrosomia and low birth weight.
ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).
Training primary care staff in delivering the primary care consultation remotely: a systematic review.

BACKGROUND Remote consultations are widely used in primary care and the levels of use have increased hugely since the onset of the Covid-19 pandemic. Despite this, primary care clinicians lack formal training in delivering these. There is a need to understand how training might best be delivered and what evidence there is to support this. AIM To summarise existing published literature about training primary care staff in conducting primary care consultation remotely, to outline which models of training may be effective and identify unanswered questions for future research. DESIGN & SETTING Systematic review of studies in primary care. METHOD Databases were searched using a pre-defined search strategy. Title, abstract and full text screening was conducted to identify eligible studies for inclusion in the review. Quality of included studies was assessed, and findings were synthesised to answer the research questions. RESULTS We included 11 studies. Seven examined training on remote consultations with trainee GPs or residents and four with qualified primary care clinicians. Training described led to overall positive change, including increased confidence and self-efficacy in delivering remote consultations. Furthermore, trainees reported increased use of remote consultations, increased efficiency and increased engagement from patients. Studies where training involved workshops or didactic learning alongside experiential learning resulted in more positive feelings and more confidence about how technology could aid consultations. CONCLUSION There is limited evidence on training primary care staff in conducting remote consultations. Available evidence indicates that training has a positive impact on clinician and staff ability to deliver remote consultation.
Metals and Monies in an Emerging Global Economy

Contents: Introduction: monetary substances in global perspective Source areas: Silver production in central Europe, 1450a "1618, John U. Nef Una forma de oposiciA^3n: el contrabando, ZacarA-as Moutoukias The production and uses of gold and silver in 16th- and 17th-century Japan, A. Kobata Exports of Japana (TM)s silver to China via Korea and changes in the Tokugawa monetary system during the 17th and 18th centuries, Tashiro Kazui The Dutch East India Company's trade in Japanese copper, 1645a "1736, Kristof Glamann A note on the relative importance of slaves and gold in west African exports, Richard Bean End markets: International bullion flows and the Chinese economy circa 1530a "1650, William S. Atwell Silver and the fall of the Ming: a reassessment, Brian Moloughney and Xia Weizhong The Cowrie currencies of West Africa, Marion Johnson A history of money in Asian perspective, Frank Perlin Born with a a "silver spoona (TM): the origin of world trade in 1571, Dennis O. Flynn and Arturo GirA! ldez Intermediary trade routes: Trade between China, the Philippines and the Americas during the 16th and 17th centuries, Chuan Hang-Sheng Amsterdam, marchA(c) mondial des mA(c)taux prA(c)cieux au XVIIe et XVIIIe siAcles, J.-G. Van Dillen World silver flows and monetary factors as a force of international economic integration, 1658a "1758, K. N. Chaudhuri The disintegration of the Ottoman monetary system during the 17th century, Sevket Pamuk Imports of treasure and Surata (TM)s trade in the 17th century, V. B. Gupta Index.
Programmed Death Ligand-1 (PD-L1) Expression in Cervical Squamous Cell Carcinoma: Does it Correlate With Outcomes?

Cervical cancer is one of the most common gynecological malignancies. Upregulation of programmed death ligand-1 (PD-L1), an immunoregulatory protein, is associated with an adverse outcomes in several malignancies. Most studies evaluating PD-L1 expression in cervical squamous cell carcinoma (CSCC) lack data on outcomes. In this study, we correlate PD-L1 expression with clinicopathologic factors and clinical outcomes in invasive CSCC. Seventy-three cases of CSCC from 2010 to 2018 were immunostained for PD-L1. A combined positive score (CPS) of ≥1 and ≥10 was correlated with age, stage, and survival outcomes. Kaplan-Meier curves for progression-free survival and overall survival were plotted and compared using the log-rank test. Cox regression analysis was performed to identify significant prognostic factors (2-tailed P<0.05 was considered statistically significant). With CPS ≥1 or ≥10 as the cut-off, PD-L1 was positive in 52/73 (71.2%) and 23/73 (31.5%) of cases, respectively. PD-L1 positive patients present at a higher stage of disease, especially those with CPS ≥10. With CPS of ≥10 as the cut-off, the 5-yr progression-free survival and 5-yr overall survival were significantly lower (P = 0.034 and 0.012, respectively). Only stage was statistically significant for worse overall survival on multivariate analysis. PD-L1 positive patients present at a higher stage of disease, and stage is an independent prognostic indicator for adverse outcomes in CSCC. This study highlights the potential of PD-L1 targeted therapy in patients with CSCC.
Mechanical thrombectomy in young patients with large vessel occlusion‐related ischemic stroke: Data from the Italian Registry of Endovascular Treatment in Acute Stroke

The weight of outcome predictors in acute ischemic stroke (AIS) patients older than 60 years is not necessarily mirrored in the younger population, posing the question of whether outcome determinants specific for the latter might vary. Very few data are available on predictors of outcome in young AIS patients receiving endovascular treatment (EVT).
Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice

Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin Cmax and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (–)-β-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (–)-β-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin Cmax by 31% and 25%, respectively, and had no effect on half-life. Berberine and (–)-β-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal–metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.
Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype–phenotype correlation

Abstract Aims Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. Methods and results Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. Conclusion LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.
Sweroside functionalized with Mesenchymal Stem cells derived exosomes attenuates sepsis-induced myocardial injury by modulating oxidative stress and apoptosis in rats

Sepsis is a life-threatening problem by organ dysfunction influenced by negative inflammatory responses and stimulated oxidative stress, which most of sepsis patients about 40–60% are accompanied with myocardial injury. Recently, stem cells derived exosomes could effectively apply in the numerous diseases by combined with natural therapeutic agents. In the present investigation, Sweroside functionalized with exosomes to control inflammatory responses by sepsis and significantly proved the function of depreciated myocardial injury-induced by LPS. The sweroside could have effectively delivered to cardiomyocytes cells via exosome carriers. The induced-SMI rats exhibited severe myocardial injury and apoptosis by in vivo experiments and treatment of sweroside-functionalized exosomes (SWO/EX) reassured the phenotypes. Importantly, SWO/EX significantly downregulated the ROS generation in the SMI rat models. The SOD and GSH activity were also suppressed in SMI rat models, and treated models with SWO/EXO could have effective liberating activity in the Rats. Meanwhile, SWO/EXO treated LPS-induced cardiomyocytes displayed that significant reduction of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) levels and also increasing cell survival and prevented apoptosis. Thus, we demonstrate that MS-cells derived exosome with sweroside could have effectively impede sepsis-induced myocardial injury. SWO/EX formulations might be applied as a potent therapeutic agent for SMI therapy.
Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study

#TAPUR results of pembrolizumab in various tumors with HTMB extend KEYNOTE-158 data that led to FDA approval in tumors with HTMB PURPOSE The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a pragmatic basket trial evaluating antitumor activity of approved targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from cohorts of patients with high tumor mutational burden (HTMB, defined as ≥9 mutations per megabase) with advanced colorectal cancer (CRC) and other advanced cancers treated with pembrolizumab are reported. METHODS Eligible patients were 18 years and older with measurable tumors and a lack of standard treatment options, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. The primary end point was disease control (DC), defined as complete or partial response or stable disease (SD) of at least 16-weeks duration. For the CRC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. Low accruing histology-specific cohorts were collapsed into one histology-pooled (HP) cohort. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included objective response (OR), safety, progression-free survival, overall survival, duration of response, and duration of SD. RESULTS Seventy-seven patients with HTMB with CRC (n = 28) or advanced cancers (n = 49) were treated with pembrolizumab. For the CRC cohort, the DC rate was 31% (P = .04) and the OR rate was 11%. For the HP cohort, the DC rate was 45% (one-sided 90% CI, 35 to 100) and the OR rate was 26%. The null hypothesis of a 15% DC rate was rejected for both cohorts. Twelve of 77 patients experienced treatment-related grade 3 adverse events (AEs) or serious AEs, including two deaths. CONCLUSION Pembrolizumab demonstrated antitumor activity in pretreated patients with advanced cancers and HTMB.
Pharmacokinetic Modeling Using Real‐World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement–Clinical Outcomes Relationship

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO), but evidence is lacking on the ideal dosing. We aimed to (1) develop a population pharmacokinetic (PK) model for UFH, measured through anti–factor Xa assay; (2) optimize UFH starting infusions and dose titrations through simulations; and (3) explore UFH exposure–clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A 1‐compartment PK model with time‐varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first‐order rate constant to reach steady‐state CL were 0.57 L/(h·10 kg) and 0.02/h. Comparable to non‐ECMO patients, the typical steady‐state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 and 20 IU/h/kg for patients aged younger than 6 years and 6 years or older, respectively, achieved the therapeutic target in 56.6% of all patients, whereas only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in more than 90% of patients while less than 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti–factor Xa target rapidly and safely.
Lung metastasis from thyroid cancer: A case report of unusual imaging presentation of lung metastases

Rationale: Thyroid cancer (TC) is the most common malignancy of the head and neck and endocrine system. Distant metastases from TC are rare and are diagnosed in only 1% to 4% of patients, and these patients have a poor prognosis, which is the leading cause of TC-related deaths. There are few reports on metastatic TC in China and abroad, and even fewer reports on lung metastases from TC. We report a special patient with lung metastases of TC. Patient concerns: The patient is a 31-year-old female who was found to have both lung nodules during physical examination. Chest computed tomography (CT) showed that the density of both lung nodules was the same as the vascular density, considering that the possibility of vascular origin was not excluded. Diagnosis: After consultation with the whole hospital, it was considered that vascular malformations, hemangiomas, and malignant metastases were not excluded, the patient percutaneous lung biopsy had a high risk of bleeding, and thoracoscopic lobectomy could be performed in thoracic surgery to further clarify the pathology and diagnosis. Outcomes: The patient underwent thoracoscopic left lower lobe wedge resection on February 24, 2021. Postoperative pathology: (left lower lung mass) metastatic carcinoma, combined with morphology and immunohistochemistry, leaning toward thyroid follicular carcinoma lung metastasis. On May 27, 2021, the patient underwent “total thyroidectomy + lymph node dissection in the right cervical VI region. ” Pathological examination: (right lobe and isthmus of the thyroid gland) papillary TC, follicular subtype, and classic type, with interstitial fibrosis. The patient was diagnosed with lung metastasis of TC. Lessons: This patient had the same CT value of lung metastases as the vascular CT value, which is relatively rare in our clinical practice and worthy of our study. The special CT imaging presentation of this TC patient with lung metastases further broadened our horizon. In clinical practice, when we encounter similar cases, we should combine more with other tests and examinations of patients to avoid misdiagnosis and missed diagnosis.
Ancestral SARS‐CoV‐2 and Omicron BA.5‐specific neutralizing antibody and T‐cell responses after Omicron bivalent booster vaccination in previously infected and infection‐naive individuals

Coronavirus disease‐2019 (COVID‐19) bivalent ancestral/Omicron messenger RNA (mRNA) booster vaccinations became available to boost and expand the immunity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron infections. In a prospective cohort study including 59 healthcare workers, we assessed SARS‐CoV‐2 ancestral and Omicron BA.5‐specific neutralizing antibody and T‐cell responses in previously infected and infection‐naive individuals. Also, we assessed the effect of an ancestral/Omicron BA.1 bivalent mRNA booster vaccination on these immune responses. 10 months after previous monovalent mRNA vaccinations, ancestral SARS‐CoV‐2 S1‐specific T‐cell and anti‐RBD IgG responses remained detectable in most individuals and a previous SARS‐CoV‐2 infection was associated with increased T‐cell responses. T‐cell responses, anti‐RBD IgG, and Omicron BA.5 neutralization activity increased after receiving an ancestral/Omicron BA.1 bivalent booster mRNA vaccination. An Omicron BA.5 infection in addition to bivalent vaccination, led to a higher ratio of Omicron BA.5 to ancestral strain neutralization activity compared to no bivalent vaccination and no recent SARS‐CoV‐2 infection. In conclusion, SARS‐CoV‐2 T‐cell and antibody responses persist for up to 10 months after a monovalent booster mRNA vaccination. An ancestral/Omicron BA.1 bivalent booster mRNA vaccination increases these immune responses and also induces Omicron BA.5 cross‐neutralization antibody activity. Finally, our data indicate that hybrid immunity is associated with improved preservation of T‐cell immunity.