A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells.

Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High-specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates.

Gut microbiota composition and metabolic characteristics in patients with Craniopharyngioma.

BACKGROUND: Emerging evidence suggests that the gut microbiota is associated with various intracranial neoplastic diseases. It has been observed that alterations in the gut microbiota are present in gliomas, meningiomas, and pituitary neuroendocrine tumors (Pit-NETs). However, the correlation between gut microbiota and craniopharyngioma (CP), a rare embryonic malformation tumor in the sellar region, has not been previously mentioned. Consequently, this study aimed to investigate the gut microbiota composition and metabolic patterns in CP patients, with the goal of identifying potential therapeutic approaches. METHODS: We enrolled 15 medication-free and non-operated patients with CP and 15 healthy controls (HCs), conducting sequential metagenomic and metabolomic analyses on fecal samples to investigate changes in the gut microbiota of CP patients. RESULTS: The composition of gut microbiota in patients with CP compared to HCs show significant discrepancies at both the genus and species levels. The CP group exhibits greater species diversity. And the metabolic patterns between the two groups vary markedly. CONCLUSIONS: The gut microbiota composition and metabolic patterns in patients with CP differ significantly from the healthy population, presenting potential new therapeutic opportunities.

Digital-Twin-Driven Intelligent Insulated-Gate Bipolar Transistor Production Lines.

With the rapid development of novel energy vehicles, power generation, photovoltaics, and other industries, power electronic devices have gained considerable attention. Insulated-gate bipolar transistors (IGBTs) have been widely used in those fields. With the emergence of intelligent manufacturing concepts such as Germany's "Industry 4.0" and China's "Made in China 2025", conventional manufacturing which needs to be upgraded with higher efficiency and yield is rapidly pivoting toward digitalization and intelligence. The digital twin methodology has been extensively used in various industries for constructing virtual models of physical entities, facilitating real-time data interconnection to reduce costs and improve efficiency. This study proposes a modular intelligent IGBT production line based on the digital twin. Real-time data are transmitted from a physical line to a digital line for storage and analysis. The digital line is visualized, and an intelligent management platform containing multiple functions is developed. Additionally, a process simulation database is established to obtain the optimal process parameters. Numerous quality issues that can arise during each process of IGBT packaging are addressed using a problem-solving approach based on the digital twin methodology. Consequently, this digital-twin-based IGBT intelligent production line effectively enhances yield rates and efficiency. IGBT modules with various packaging forms such as ACF, ACE, and ACD are manufactured.

The Mechanism of Short-Circuit Oscillations in Automotive-Grade Multi-Chip Parallel Power Modules and an Effective Mitigation Approach.

This paper presents an in-depth analysis of the oscillation phenomenon occurring in multi-chip parallel automotive-grade power modules under short-circuit conditions and investigates three suppression methods. We tested and analyzed two commercial automotive-grade power modules, one containing two chips and the other containing a single chip, and found that short-circuit gate oscillations were more likely to occur in multi-chip parallel packaged modules than in single-chip packaged modules. Through experimental and simulation analyses, we observed that gate oscillations were mainly caused by the interaction between internal parasitic parameters of the module and the external drive circuit, and we found that high drive resistance and low common emitter inductance between parallel chips could effectively suppress gate voltage oscillations. We also analyzed the two mainstream suppression schemes, increasing the drive gate resistance and placing the drive capacitors in parallel. Unfortunately, we found that these suppression schemes were not ideal solutions because both schemes changed the switching characteristics of the power module. As an alternative, we propose a simple and effective solution that involves adding parallel connections between the parallel chips. Simulation calculations showed that this optimized method reduced the emitter inductance between parallel chips in the upper bridge arm by about 30% and in the lower bridge arm by 35%. Through short-circuit experiments conducted at different DC bus voltages, it has been verified that the new optimized solution effectively resolves gate oscillation issues without affecting the switching characteristics of the power module.

Sodium Dynamics in the Cellular Environment.

Sodium ions are essential for the functions of biological cells, and they are maintained at the balance between intra- and extracellular environments. The quantitative assessment of intra- and extracellular sodium as well as its dynamics can provide crucial physiological information on a living system. 23Na nuclear magnetic resonance (NMR) is a powerful and noninvasive technique to probe the local environment and dynamics of sodium ions. However, due to the complex relaxation behavior of the quadrupolar nucleus in the intermediate-motion regime and because of the heterogeneous compartments and diverse molecular interactions in the cellular environment, the understanding of the 23Na NMR signal in biological systems is still at the early stage. In this work, we characterize the relaxation and diffusion of sodium ions in the solutions of proteins and polysaccharides, as well as in the in vitro samples of living cells. The multi-exponential behavior of 23Na transverse relaxation has been analyzed according to the relaxation theory to derive the crucial information related to the ionic dynamics and molecular binding in the solutions. The bi-compartment model of transverse relaxation and diffusion measurements can corroborate each other to quantify the fractions of intra- and extracellular sodium. We show that 23Na relaxation and diffusion can be used to monitor the viability of human cells, which offers versatile NMR metrics for in vivo studies.

NUAK1 promotes tumor metastasis through upregulating slug transcription in esophageal squamous cell carcinoma.

BACKGROUND: Metastasis is still a major cause of poor pathological outcome and prognosis in esophageal squamous cell carcinoma (ESCC) patients. NUAK1 has been reported highly expressed in many human cancers and is associated with the poor prognosis of cancer patients. However, the role of NUAK1 and its underlying signaling mechanism in ESCC metastasis remain unclear. METHODS: Expression of NUAK1 in ESCC was detected by real-time quantitative RT-PCR (qRT-PCR), Western blotting and immunohistochemical staining. MTT, colony formation, wound-healing and transwell assays were used to determine the role NUAK1 in vitro. Metastasis was evaluated by use of an experimental pulmonary metastasis model in BALB/c-nu/nu mice. The mechanisms were assessed by using coimmunoprecipitation, immunofluorescence and dual-luciferase reporter gene experiments. RESULTS: NUAK1 was highly expressed in ESCC tissues compared with the adjacent normal esophageal epithelial tissues. Moreover, the elevated expression of NUAK1 positively correlated with tumor invasion depth, lymph node metastasis, pathological TNM stage, and poor survival in ESCC patients. Further experiments showed that NUAK1 overexpression did not change the cell viability and colony formation of ESCC cells, while remarkably promoted the migration and invasion in vitro and experimental pulmonary metastasis in vivo. Mechanistically, NUAK1 enhanced the transcription level of Slug, which enhanced the migratory and invasive capability of ESCC cells. Consistently, silencing Slug almost completely diminished the migration and invasion of NUAK1-overexpressing ESCC cells. Further studies demonstrated that NUAK1 upregulated the transcription activity of Slug through activating the JNK/c-Jun pathway. CONCLUSION: These results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.

CT and MRI measurements of tibial tubercle lateralization in patients with patellar dislocation were not equivalent but could be interchangeable.

PURPOSE: To compare the values and the relationship of tibial tubercle lateralization measurements between computerized tomography (CT) and magnetic resonance imaging (MRI). METHODS: Sixty patients with patellar dislocation who underwent both CT and MRI of the same knee joint from November 2021 to February 2022 were included in our study. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed to evaluate the reliability of tibial tubercle-trochlear groove (TT-TG), tibial tubercle-Roman arch (TT-RA), and tibial tubercle-posterior cruciate ligament (TT-PCL) distance measurements. The values of CT and MRI measurements using the same bony landmarks were compared for the difference. Pearson correlation analysis and linear regression analysis were performed to assess the correlation between CT and MRI measurements. Finally, the estimated values obtained from the regression equation were compared with the actual values obtained from the radiological measurement to evaluate the accuracy of the equations. RESULTS: A total of 60 patients with patellar dislocation who underwent both CT and MRI of the same knee joint were included in this study. The included measurements showed excellent agreement with ICCs > 0.9. TT-TG distance measured on CT (19.5 ± 5.1 mm) had a mean of 7.1 mm higher than that on MRI (12.4 ± 4.7 mm) (P < 0.001). The mean value of TT-RA distance was 22.5 ± 3.7 mm on CT and 16.7 ± 4.9 mm on MRI (P < 0.001), showing a mean difference of 5.8 mm. The values of TT-TG distance measured by CT and MRI were significantly correlated (R = 0.5, P < 0.001). The values of TT-RA distance between these two modalities showed a better correlation than that of TT-TG distance (R = 0.6, P < 0.001). The interchange values of TT-TG distance and TT-RA distance between CT and MRI can be obtained using regression equations (TT-TG distance: y = 0.6x + 12.3; TT-RA distance: y = 0.5x + 14.4). CONCLUSION: The values of tibial tubercle lateralization measured by MRI may be underestimated compared with those measured by CT. Although the values measured on CT and MRI are not equivalent, the value in the other modality can be estimated. Therefore, an additional CT scan for tibial tubercle lateralization evaluation may not be necessary. LEVEL OF EVIDENCE: Level II.

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of <1%. Compared to the nasal retina, 10, 25 and 61 significantly regulated proteins were found in the temporal retina at 1, 4, and 8 weeks, respectively (p < 0.05, FC ≥ 1.4 or ≤0.7). Eight proteins (ALDH1A1, TRY10, GFAP, HBB-B1, ALB, CDC42, SNCG, NEFL) were differentially expressed for at least two time points. The expressions of ALDH1A1 and SNCG at nerve fibers were decreased along with axonal loss. Increased ALDH1A1 localization in the inner nuclear layer suggested stress response. Increased GFAP expression demonstrated regional reactivity of astrocytes and Muller cells. Meta-analysis of gene ontology showed a pronounced difference in endopeptidase and peptidase inhibitor activity. Temporal proteomic profiling demonstrates established and novel protein targets associated with RGC damage.

Panscleritis After Blunt Ocular Trauma in A Child with Epididymitis.

We reported an 8-year-old boy with panscleritis in left eye and right epididymitis after falling on the ground. Etiologic diagnosis played a key role in this case. Systemic examinations ruled out systemic autoimmune diseases, tumors, and infections as the cause of scleritis and suggested that the disease was caused by a local delayed-type hypersensitivity (DTH) induced by ocular trauma and was non-infectious. Still, the right epididymitis was infectious. Both conditions were treated successfully using steroids and antibiotics, respectively. Thus, early etiologic diagnosis and reasonable treatment are crucial to prevent visual loss.

Accurate de novo design of hyperstable constrained peptides.

Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for accurate de novo design of conformationally restricted peptides, and the use of these methods to design 18-47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N-C backbone-cyclized. Both genetically encodable and non-canonical peptides are exceptionally stable to thermal and chemical denaturation, and 12 experimentally determined X-ray and NMR structures are nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.

Higher pathologic threshold of increased tibial tuberosity-trochlear groove distance should be considered for taller patients.

PURPOSE: The aim of this study was to evaluate the correlation between tibial tuberosity-trochlear groove distance (TT-TG) and body height or knee size, and to find height-related pathologic thresholds of increased TT-TG. METHODS: One-hundred and fifty-three patients with recurrent patellar instability and 151 controls were included. The TT-TG was measured on axial computed tomography (CT) images. Femora width and tibial width were selected to represent knee size. The correlation of TT-TG and gender, body height, femora width, and tibial width was evaluated. The height-related pathologic threshold of increased TT-TG was produced according to Dejour's method. To combine TT-TG with body height and knee size, three new indexes were introduced, ratio of TT-TG to body height (RTH), ratio of TT-TG to femoral width (RTF), and ratio of TT-TG to tibial width (RTT). The ability to predict patellar instability was assessed by the receiver-operating characteristic (ROC) curve, odds ratios (ORs), sensitivity, and specificity. RESULTS: In patients with patellar instability, TT-TG showed significantly correlation with patient height, femoral width, and tibial width respectively (range r = 0.266-0.283). This correlation was not found in the control group. The pathologic threshold of TT-TG was 18 mm in patients < 169 cm (53%), and the mean TT-TG was 21 mm in patients ≥ 169 cm (54%). There was significant difference in RTH, RTF, and RTT between the two groups. RTH, RTF and RTT have similar large area under the curve (AUC) with TT-TG. CONCLUSIONS: TT-TG showed significant correlation with body height and knee size, respectively. The pathologic threshold of increased TT-TG was suggested to be 21 mm for patients [Formula: see text] 169 cm and 18 mm for patients [Formula: see text] 169 cm. Body height-related pathologic threshold provided a supplement for indications of tibial tuberosity medialization. LEVEL OF EVIDENCE: IV.

3' UTR lengthening as a novel mechanism in regulating cellular senescence.

Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3' untranslated regions (3' UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3' UTRs and reduced gene expression. Genes that harbor longer 3' UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3' UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3' UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

Tibial Tubercle Osteotomy May Not Provide Additional Benefit in Treating Patellar Dislocation With Increased Tibial Tuberosity-Trochlear Groove Distance: A Systematic Review.

PURPOSE: To examine the indications and outcomes of medial patellofemoral ligament reconstruction (MPFLR) with or without tibial tubercle osteotomy (TTO) in treating recurrent or habitual patellar dislocation with an increased tibial tuberosity-trochlear groove (TT-TG) distance. METHODS: We performed a literature search of the established medical databases Cochrane Central, PubMed-MEDLINE, EMBASE, and Web of Science. The inclusion criteria were as follows: skeletally mature patients with recurrent or habitual patellar dislocation and an increased TT-TG distance, treatment with MPFLR combined with a TTO procedure or isolated MPFLR, and reporting of clinical outcomes and complications. Each study was assessed for quality and the level of evidence. The general characteristics, indications, surgical techniques, TT-TG distance, clinical results, imaging evaluation findings, and complications of each study were recorded. RESULTS: Nine studies consisting of 288 knees met the inclusion criteria. The average Coleman score was 71.56 (range, 55-83). The threshold for an increased TT-TG distance ranged from 16 to 20 mm in the included studies. Similar good postoperative outcomes were reported in patients with an increased TT-TG distance treated with MPFLR with versus without a TTO procedure. The mean postoperative Lysholm score ranged from 75.0 to 94.7 (I2 = 87.6%) in the isolated MPFLR group and from 85.0 to 87.6 (I2 = 16.3%) in the TTO-with-MPFLR group. Similar postoperative congruence angles were reported in both groups. The postoperative redislocation rate ranged from 0% to 4.2% in the TTO-with-MPFLR group, and no redislocation was found in the isolated MPFLR group. The postoperative apprehension sign was only reported in isolated MPFLR patients. CONCLUSIONS: The outcomes of MPFLR with or without TTO to treat recurrent or habitual patellar dislocation with an increased TT-TG distance appeared similar. However, this study was limited by the considerable heterogeneity, variety of techniques, variety of TT-TG distances, and variability in patella alta and trochlear dysplasia among the included studies. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies.

Using Anatomic Landmarks to Locate Schöttle's Point Was Accurate Without Fluoroscopy During Medial Patellofemoral Ligament Reconstruction.

PURPOSE: The purpose of the present study was to analyze the anatomic landmarks of Schöttle's point and establish a locating method for identification. METHODS: From 2013 to 2016, patients undergoing medial patellofemoral ligament (MPFL) reconstruction for patellofemoral instability were enrolled. INCLUSION CRITERIA: at least 2 episodes of patellar dislocation. EXCLUSION CRITERIA: previous knee surgeries, open physes, severe trochlear dysplasia， tibial tuberosity lateralization, or patella alta. Group A: From January 2013 to December 2013, preoperative 3-dimensional computed tomography (3D-CT) images were obtained. Anatomic features of Schöttle's point were measured on the 3D-CT images. A Schöttle's point locating method with 2 distinct landmarks was established. Group B: From January 2014 to January 2016, consecutive MPFL reconstructions were performed. The placement of Schöttle's point was following the established method without fluoroscopy. The accuracy of femoral tunnel positions was assessed on the 3D-CT images postoperatively. RESULTS: CT images of 53 knees were obtained in group A. Forty-seven MPFL reconstructions were performed in group B. No significant difference was found between the 2 groups regarding to demographic characteristics. The intraclass correlation coefficients were excellent for all measures (r = 0.97). In group A, Schöttle's point was 8.1 ± 0.2 mm (95% confidence interval [CI], 7.7-8.5) distal to the apex of the adductor tubercle and 8.0 ± 0.3 mm (95% CI, 7.4-8.6) anterior to the posterior edge. Apex of the adductor tubercle was defined as the most convex point, and posterior edge was defined as the edge of the posteromedial cortex in the transition area between the medial condyle and femoral shaft. In group B, 44 of 47 femoral tunnels (93.6%) were considered localized in the proper zone. CONCLUSIONS: Schöttle's point was approximately 8 mm distal to the apex of the adductor tubercle and 8 mm from the posterior edge. Schöttle's point locating method without fluoroscopy had high accuracy. LEVEL OF EVIDENCE: Level IV, case series.

The adaptability of H9N2 avian influenza A virus to humans: A comparative docking simulation study.

Influenza A virus, the H9N2 subtype, is an avian influenza virus that has long been circulating in the worldwide poultry industry and is occasionally found to be transmissible to humans. Evidence from genomic analysis suggests that H9N2 provides the genes for the H5N1 and H7N9 subtypes, which have been found to infect mammals and pose a threat to human health. However, due to the lack of a structural model of the interaction between H9N2 and host cells, the mechanism of the extensive adaptability and strong transformation capacity of H9N2 is not fully understood. In this paper, we collected 40 representative H9N2 virus samples reported recently, mainly in China and neighboring countries, and investigated the interactions between H9N2 hemagglutinin and the mammalian receptor, the polysaccharide α-2,6-linked lactoseries tetrasaccharide c, at the atomic level using docking simulation tools. We categorized the mutations of studied H9N2 hemagglutinin according to their effects on ligand-binding interactions and the phylogenetic analysis. The calculations indicated that all the studied H9N2 viruses can establish a tight binding with LSTc although the mutations caused a variety of perturbations to the local conformation of the binding pocket. Our calculations suggested that a marginal equilibrium is established between the conservative ligand-receptor interaction and the conformational dynamics of the binding pocket, and it might be this equilibrium that allows the virus to accommodate mutations to adapt to a variety of environments. Our results provided a way to understand the adaptive mechanisms of H9N2 viruses, which may help predict its propensity to spread in mammals.

Cytotoxicity of safrole in HepaRG cells: studies on the role of CYP1A2-mediated ortho-quinone metabolic activation.

1. Safrole is a natural compound categorized as a group 2B carcinogen extracted from sassafras oil or certain other essential oils. The hepatotoxicity of safrole has always been highly concerned. So, the purpose of this study was to evaluate the role of cytochrome P450 (CYP450)-mediated reactive metabolites (RMs) formation and its induced cytotoxicity in HepaRG cells. 2. Safrole belongs to the methylenedioxyphenyl structure which could be activated to RMs. Two metabolites (M1, M2) and three new glutathione conjugates (M3-M5) of safrole ortho-oquinone RMs were found in HepaRG cells. Using human recombinant CYP450 enzymes and chemical inhibitor method, the metabolism of safrole RMs was predominantly carried out through the CYP1A2 with minor contributions by CYP2E1. 3. Induction of CYP1A2 by omeprazole (OME) enhanced safrole-induced cytotoxicity, compared with treatment with safrole alone, whereas inhibition of CYP1A2 by alpha-naphthoflavone (α-NAP) decreased the cytotoxicity. The cytotoxicity of cell induced by safrole was related to the amount of RMs formation. Besides, pretreatment with L-buthionine sulfoximine (BSO) to deplete intracellular GSH markedly enhanced safrole-induced cytotoxicity. OME induced the safrole-induced GSH exhaustion, and GSH depletion by safrole was not via oxidation of GSH and occurred prior to the increase in ROS. Furthermore, mitochondrial membrane potential (ΔΨm) could be aggravated by the inducer of CYP1A2 together with safrole. Collectively, these data suggest that the ortho-quinone RM may mediate safrole hepatotoxicity, and CYP1A2 was the core enzyme in ortho-quinone RMs-mediated safrole hepatotoxicity.

Position-specific intron retention is mediated by the histone methyltransferase SDG725.

BACKGROUND: Intron retention (IR), the most prevalent alternative splicing form in plants, plays a critical role in gene expression during plant development and stress response. However, the molecular mechanisms underlying IR regulation remain largely unknown. RESULTS: Knockdown of SDG725, a histone H3 lysine 36 (H3K36)-specific methyltransferase in rice, leads to alterations of IR in more than 4700 genes. Surprisingly, IR events are globally increased at the 5' region but decreased at the 3' region of the gene body in the SDG725-knockdown mutant. Chromatin immunoprecipitation sequencing analyses reveal that SDG725 depletion results in a genome-wide increase of the H3K36 mono-methylation (H3K36me1) but, unexpectedly, promoter-proximal shifts of H3K36 di- and tri-methylation (H3K36me2 and H3K36me3). Consistent with the results in animals, the levels of H3K36me1/me2/me3 in rice positively correlate with gene expression levels, whereas shifts of H3K36me2/me3 coincide with position-specific alterations of IR. We find that either H3K36me2 or H3K36me3 alone contributes to the positional change of IR caused by SDG725 knockdown, although IR shift is more significant when both H3K36me2 and H3K36me3 modifications are simultaneously shifted. CONCLUSIONS: Our results revealed that SDG725 modulates IR in a position-specific manner, indicating that H3K36 methylation plays a role in RNA splicing, probably by marking the retained introns in plants.

Hemostatic techniques to reduce blood transfusion after primary TKA: a meta-analysis and systematic review.

PURPOSE: To investigate the efficacy of non-tranexamic acid (TXA) on reducing blood loss and requirements of allogeneic blood transfusion (ABT) in total knee arthroplasty (TKA). METHODS: The PubMed, EMBASE, and the Cochrane Library databases were researched since incipiency to June 2018. Only randomized controlled trials (RCTs) involved with non-TXA hemostatic techniques in TKA met the inclusion criteria. RESULTS: A total of 36 RCTs, including 1511 patients, were recruited for analysis. The results of subgroup analysis revealed that hemostatic techniques, which could substantially decrease the rate of ABT, were cell salvage with the transfusion trigger of 9 mg/dl, fibrin sealant with a dosage of 10 ml, and postoperative flexion position. CONCLUSION: The available evidence in this meta-analysis suggests that postoperative flexion position, fibrin sealant, and cell salvage can substantially decrease the rate of ABT in TKA. Further studies, including more hemostatic methods and high-quality research, are expected.

Sequence-based prediction of physicochemical interactions at protein functional sites using a function-and-interaction-annotated domain profile database.

BACKGROUND: Identifying protein functional sites (PFSs) and, particularly, the physicochemical interactions at these sites is critical to understanding protein functions and the biochemical reactions involved. Several knowledge-based methods have been developed for the prediction of PFSs; however, accurate methods for predicting the physicochemical interactions associated with PFSs are still lacking. RESULTS: In this paper, we present a sequence-based method for the prediction of physicochemical interactions at PFSs. The method is based on a functional site and physicochemical interaction-annotated domain profile database, called fiDPD, which was built using protein domains found in the Protein Data Bank. This method was applied to 13 target proteins from the very recent Critical Assessment of Structure Prediction (CASP10/11), and our calculations gave a Matthews correlation coefficient (MCC) value of 0.66 for PFS prediction and an 80% recall in the prediction of the associated physicochemical interactions. CONCLUSIONS: Our results show that, in addition to the PFSs, the physical interactions at these sites are also conserved in the evolution of proteins. This work provides a valuable sequence-based tool for rational drug design and side-effect assessment. The method is freely available and can be accessed at http://202.119.249.49 .

From hadrons to quarks in neutron stars: a review.

In recent years our understanding of neutron stars has advanced remarkably, thanks to research converging from many directions. The importance of understanding neutron star behavior and structure has been underlined by the recent direct detection of gravitational radiation from merging neutron stars. The clean identification of several heavy neutron stars, of order two solar masses, challenges our current understanding of how dense matter can be sufficiently stiff to support such a mass against gravitational collapse. Programs underway to determine simultaneously the mass and radius of neutron stars will continue to constrain and inform theories of neutron star interiors. At the same time, an emerging understanding in quantum chromodynamics (QCD) of how nuclear matter can evolve into deconfined quark matter at high baryon densities is leading to advances in understanding the equation of state of the matter under the extreme conditions in neutron star interiors. We review here the equation of state of matter in neutron stars from the solid crust through the liquid nuclear matter interior to the quark regime at higher densities. We focus in detail on the question of how quark matter appears in neutron stars, and how it affects the equation of state. After discussing the crust and liquid nuclear matter in the core we briefly review aspects of microscopic quark physics relevant to neutron stars, and quark models of dense matter based on the Nambu-Jona-Lasinio framework, in which gluonic processes are replaced by effective quark interactions. We turn then to describing equations of state useful for interpretation of both electromagnetic and gravitational observations, reviewing the emerging picture of hadron-quark continuity in which hadronic matter turns relatively smoothly, with at most only a weak first order transition, into quark matter with increasing density. We review construction of unified equations of state that interpolate between the reasonably well understood nuclear matter regime at low densities and the quark matter regime at higher densities. The utility of such interpolations is driven by the present inability to calculate the dense matter equation of state in QCD from first principles. As we review, the parameters of effective quark models-which have direct relevance to the more general structure of the QCD phase diagram of dense and hot matter-are constrained by neutron star mass and radii measurements, in particular favoring large repulsive density-density and attractive diquark pairing interactions. We describe the structure of neutron stars constructed from the unified equations of states with crossover. Lastly we present the current equations of state-called 'QHC18' for quark-hadron crossover-in a parametrized form practical for neutron star modeling.