Miracle-dz/UniFAR-FTUs huggingface dataset:
A Century of Insulin: Outstanding Physiological Breakthroughs.

This year, the global research community is commemorating 100th year anniversary of the landmark achievement by Fredrick G. Banting, Charles Best, James B. Collip, and John R. MacLeod, a group of scientists from the University of Toronto who conducted critical experiments that led to the discovery of insulin, which was later shown by the group to reverse deadly metabolic consequences of diabetes mellitus (1). The origins of physiological research into insulin-mediated control of glucose homeostasis date back to the latter half of the 19th century driven by the seminal detection of pancreatic islets by the German medical student Paul Langerhans. This discovery was followed by a wave of pioneering work by European and American physiologists at the turn of the 20th century (notably von Mering and Oscar Minkowski and Nicolae Paulescu) that fittingly postulated the involvement of pancreatic islets in the regulation of carbohydrate metabolism (2), thus paving the way for the discovery of what would be later known as insulin by Banting and his colleagues in 1921 (1). Although prior researchers had made pivotal contributions toward characterization of the pancreatic effects on glucose metabolism, the work by Banting, Best, Collip, and MacLeod almost immediately demonstrated therapeutic efficacy of insulin for the treatment of diabetes mellitus, thus opening a much-needed opportunity for mass production and commercialization of insulin as a life-saving medical treatment. Indeed, life-saving advances in insulin therapy are highlighted by a seminal Epidemiology of Diabetes Interventions and Complications trial that demonstrated that modern mortality rates in patients with Type 1 diabetes treated with intensive insulin therapy are essentially indistinguishable from those observed in the general population (3). In addition to the obvious significance of discovering and implementing a treatment of diabetes, the work of Banting et al. ushered in an era of experimental research into insulin’s role in the regulation of essential physiological (e.g., nutrient metabolism, reproduction, growth, etc.) and pathophysiological (e.g., diabetes, obesity, cancer, neurodegeneration) conditions. Indeed, the majority of “early” work in this area was performed by trained physiologists, pioneered by the leadership of John Macleod, Professor of Physiology, and the enrollment of Charles Best as a physiology graduate student at the University of Toronto. Correspondingly, this editorial discusses some of the key physiological discoveries and advances related to the regulation of insulin’s action, secretion, and therapeutics, as well as future implications arising from this trailblazing physiological research conducted over the past 100 years (FIGURE 1).
KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
On the time‐varying predictive performance of longitudinal biomarkers: Measure and estimation

In many biomedical studies, participants are monitored at periodic visits until the occurrence of the failure event. Biomarkers are often measured repeatedly during these visits, and such measurements can facilitate updated disease prediction. In this work, we propose a two‐dimensional incident dynamic area under curve (AUC), to capture the variability due to both the biomarker assessment time and the prediction time to comprehensively quantify the predictive performance of a longitudinal biomarker. We propose a pseudo partial‐likelihood to achieve consistent estimation of the AUC under two realistic scenarios of visit schedules. Variance estimation methods are designed to facilitate inferential procedures. We examine the finite‐sample performance of our method through extensive simulations. The methods are applied to a study of chronic myeloid leukemia to evaluate the predictive performance of longitudinally collected gene expression levels.
Reversing Antibiotic Resistance Caused by Mobile Resistance Genes of High Fitness Cost

The dissemination of bacterial antibiotic resistance is a serious threat to human health. The development of new antibiotics faces both economic and technological challenges. ABSTRACT The reversibility of antibiotic resistance is theoretically attractive due to the prospect of restoring the clinical potency of antibiotics. It is important to find out the factors that affect the reversibility of antibiotic resistance. Here, an mcr-1-positive multidrug-resistant (MDR) environmental Escherichia coli isolate was successively passaged under four antibiotic-free culture conditions. The relative abundances of multiple antibiotic resistance genes (ARGs) kept decreasing during the successive passages. The linear correlations between abundances of ARGs on the same MDR plasmid reflected that the decay of antibiotic resistance during the passage was mainly due to the elimination of the MDR plasmid (pMCR_W5-6). Colistin-susceptible strains were isolated at the end of the passage. The whole-genome sequencing of two susceptible isolates detected the elimination of the MDR plasmid and deletion of the mcr-1 gene. Deletions of DNA fragments from chromosome and plasmid were closely related to a variety of insertion sequences (ISs). The results of coculture of resistant and susceptible strains at different antibiotic concentrations indicated that the high fitness cost led to the poor stability of mobile ARGs. Strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. IMPORTANCE The dissemination of bacterial antibiotic resistance is a serious threat to human health. The development of new antibiotics faces both economic and technological challenges. The reversibility of antibiotic resistance has become an important issue causing wide concern due to the prospect of restoring the clinical potency of antibiotics. Our study suggests that the high mobility of ARGs of high fitness cost may just reflect their poor stability. Therefore, strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. This study brings hope for the possibility of curbing the dissemination of antibiotic resistance.
Endothelial STING controls T cell transmigration in an IFNI-dependent manner

The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING–/– mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING–/– T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell–expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α–stimulated STING–/– EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.
Functional connectome fingerprint of holistic–analytic cultural style

Abstract Although research in the field of cultural psychology and cultural neuroscience has revealed that culture is an important factor related to the human behaviors and neural activities in various tasks, it remains unclear how different brain regions organize together to construct a topological network for the representation of individual’s cultural tendency. In this study, we examined the hypothesis that resting-state brain network properties can reflect individual’s cultural background or tendency. By combining the methods of resting-state magnetic resonance imaging and graph theoretical analysis, significant cultural differences between participants from Eastern and Western cultures were found in the degree and global efficiency of regions mainly within the default mode network and subcortical network. Furthermore, the holistic–analytic thinking style, as a cultural value, provided a partial explanation for the cultural differences on various nodal metrics. Validation analyses further confirmed that these network properties effectively predicted the tendency of holistic–analytic cultural style within a group (r = 0.23) and accurately classified cultural groups (65%). The current study establishes a neural connectome representation of holistic–analytic cultural style including the topological brain network properties of regions in the default mode network, the basal ganglia and amygdala, which enable accurate cultural group membership classification.
Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder

SYNCRIP encodes for the Synaptotagmin‐binding cytoplasmic RNA‐interacting protein, involved in RNA‐binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic‐atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA‐binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype‐phenotype correlations. Our study provides further evidence for a SYNCRIP‐associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic‐atonic epilepsy.
View-Aware Geometry-Structure Joint Learning for Single-View 3D Shape Reconstruction

Reconstructing a 3D shape from a single-view image using deep learning has become increasingly popular recently. Most existing methods only focus on reconstructing the 3D shape geometry based on image constraints. The lack of explicit modeling of structure relations among shape parts yields low-quality reconstruction results for structure-rich man-made shapes. In addition, conventional 2D-3D joint embedding architecture for image-based 3D shape reconstruction often omits the specific view information from the given image, which may lead to degraded geometry and structure reconstruction. We address these problems by introducing VGSNet, an encoder-decoder architecture for view-aware joint geometry and structure learning. The key idea is to jointly learn a multimodal feature representation of 2D image, 3D shape geometry and structure so that both geometry and structure details can be reconstructed from a single-view image. To this end, we explicitly represent 3D shape structures as part relations and employ image supervision to guide the geometry and structure reconstruction. Trained with pairs of view-aligned images and 3D shapes, the VGSNet implicitly encodes the view-aware shape information in the latent feature space. Qualitative and quantitative comparisons with the state-of-the-art baseline methods as well as ablation studies demonstrate the effectiveness of the VGSNet for structure-aware single-view 3D shape reconstruction.
Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model. Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes. Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups. Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.
Efficacy of Benson’s Relaxation Technique on Anxiety and Depression among Patients Undergoing Hemodialysis: A Systematic Review

This study aimed to evaluate the efficacy of Benson’s relaxation technique on anxiety and depression among patients undergoing hemodialysis. A systematic review of randomized controlled trials was conducted. Searching databases included EBSCO Host, PubMed, ProQuest, Science Direct, Sage Journals, Ovid, and Google Scholar from January 2000 to September 2020. Five randomized controlled trials were identified. Findings revealed a statistically significant decrease in anxiety score. Concerning depression; one RCT showed a statistically significant decrease and two RCTs revealed a non-significant difference in depression level. The overall quality of the RCTs was not high. Despite that the RCTs showed benefits of BRT in managing anxiety. However, this is not the same for depression. The lack of high-quality scientific evidence supporting its retinue use indicates that additional well designed randomized controlled trials in multiple countries are warranted to support the efficacy of Benson’s relaxation technique on anxiety and depression among patients undergoing hemodialysis.
A sensitive LC/MS/MS method for the determination of glycyrrhetic acid in human plasma and application to pharmacokinetic study

Aim To establish a LC-MS-MS method for the determination of glycyrrhetic acid(GA),a major metabolite of glycyrrhizin(GLY) in human plasma,and to investigate the pharmacokinetics of GA in Glycyrrhizinate Capsules in Chinese healthy volunteers.Methods Glycyrrhizinate Capsules were orally administrated to healthy volunteers at a single dose of 150 mg.Blood samples were then collected and extracted by ethyl acetate.GA and internal standard(IS),prednisolone,were subjected to LC-MS/MS analysis with electro-spray ionization(ESI) in the multiple reaction monitoring(MRM) mode.Chromatographic separation was performed on an Agilent ZORBAX SB C18(3.0 mm×100 mm id,5 μm) within 5 min,with the mobile phase of methanol ∶ acetonitrile ∶ water(15 ∶ 60 ∶ 25,V ∶ V ∶ V) containing 0.2% acetic acid and 5 mmol·L-1ammonium acetate.The precursor to produce transitions monitored for GA and IS were m/z 469.4→355.2 and 358.9→279.9 respectively.Results Calibration curves were linear(r2 0.995) over the concentration range from 1.5 to 192 μg·L-1 for GA with the absolution recovery greater than 78.0%. The pharmacokinetic parameters after a single dose were as follows:(73.85±25.25)μg·L-1(Cmax),11.50 ±3.07 h(Tmax),(11.82 ±3.56) h(T1 2β),(1252.49±489.06)μg·h·L-1(AUC0-60). Conclusion The assay method is proved to be sensitive,accurate and convenient.It can be applied to the pharmacokinetic study of glycyrrhetic acid.The peak time of GLY in human is long after taking Glycyrrhizinate Capsule orally.The drug-time curve appears double peak in about 50% of healthy volunteers.
Aged soils contribute little to contemporary carbon cycling downstream of thawing permafrost peatlands

Vast stores of millennial‐aged soil carbon (MSC) in permafrost peatlands risk leaching into the contemporary carbon cycle after thaw caused by climate warming or increased wildfire activity. Here we tracked the export and downstream fate of MSC from two peatland‐dominated catchments in subarctic Canada, one of which was recently affected by wildfire. We tested whether thermokarst bog expansion and deepening of seasonally thawed soils due to wildfire increased the contributions of MSC to downstream waters. Despite being available for lateral transport, MSC accounted for ≤6% of dissolved organic carbon (DOC) pools at catchment outlets. Assimilation of MSC into the aquatic food web could not explain its absence at the outlets. Using δ13C‐Δ14C‐δ15N‐δ2H measurements, we estimated only 7% of consumer biomass came from MSC by direct assimilation and algal recycling of heterotrophic respiration. Recent wildfire that caused seasonally thawed soils to reach twice as deep in one catchment did not change these results. In contrast to many other Arctic ecosystems undergoing climate warming, we suggest waterlogged peatlands will protect against downstream delivery and transformation of MSC after climate‐ and wildfire‐induced permafrost thaw.
Progress in survival in renal cell carcinoma through 50 years evaluated in Finland and Sweden

Global survival studies have shown favorable development in renal cell carcinoma (RCC) treatment but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed RCC survival in Finland and Sweden over a 50-year period (1967–2016) using data from the NORDCAN database provided by the local cancer registries. While the health care systems are largely similar in the two countries, the economic resources have been stronger in Sweden. In addition to the standard 1- and 5-year relative survival rates, we calculated the difference between these as a measure of how well survival was maintained between years 1 and 5. Relative 1- year survival rates increased almost linearly in both countries and reached 90% in Sweden and 80% in Finland. Although 5-year survival also developed favorably the difference between 1- and 5-year survival rates did not improve in Sweden suggesting that the gains in 5-year survival were entirely due to gains in 1-year survival. In Finland there was a gain in survival between years 1 and 5, but the gain in 1-years survival was the main contributor to the favorable 5-year survival. Age group specific analysis showed large survival differences, particularly among women. Towards the end of the follow-up period the differences narrowed but the disadvantage of the old patients remained in 5-year survival. The limitations of the study were lack of information on performed treatment and clinical stage in the NORDCAN database. In conclusion, the available data suggest that earlier diagnosis and surgical treatment of RCC have been the main driver of the favorable change in survival during the past 50 years. The main challenges are to reduce the age-specific survival gaps, particularly among women, and push survival gains past year 1.
Radial nerve palsy following humeral shaft fracture: a theoretical PNF rehabilitation approach for tendon and nerve transfers

ABSTRACT Background Humerus fracture-induced radial nerve injury can create severe and permanent disabilities. Purpose Surgical management often relies on either tendon or nerve transfer. Regardless of which procedure is selected, physical therapists are challenged to restore functional outcomes without jeopardizing repair healing. Through synergistic, multi planar upper extremity movement patterns, neuromuscular irradiation, or overflow, and neuroplasticity, proprioceptive neuromuscular facilitation (PNF) may improve strength, range of motion and tone. Methods After reviewing the literature, a five phase PNF-based treatment approach is proposed with timing differences based on the selected procedure. Findings Phase I (2 or 4 weeks pre-surgery for tendon or nerve transfer, respectively) consists of comprehensive patient education; Phase II (4–6 or 1–2 weeks post-surgery for tendon or nerve transfer, respectively) explores variable duration peripheral and central nervous system motor learning during isometric activation to enhance central neuroplasticity; Phase III (7–12 or 3–20 weeks post-surgery for tendon or nerve transfer, respectively) incorporates low-intensity motor control including contralateral isotonic upper extremity loading to maximize overflow and neuroplastic effects; Phase IV (13–26 or 21–52 weeks post-surgery for tendon or nerve transfer, respectively) adds high-intensity strength and motor control using ipsilateral isotonic upper extremity loading to maximize overflow and neuroplastic effects. Phase V (27–52 or 53–78 weeks post-surgery for tendon or nerve transfer, respectively) progresses to more activity of daily living, vocational, or sport-specific training with higher intensity strength and motor control tasks. Conclusions Through manually guided synergistic, multi planar movement, overflow, and neuroplasticity, a PNF treatment approach may optimize neuromuscular recovery. Validation strategies to confirm clinical treatment efficacy are discussed.