Heterologous survey of 130 DNA transposons in human cells highlights their functional divergence and expands the genome engineering toolbox.

Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.

Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers.

Messenger RNA vaccines lack specificity for dendritic cells (DCs)-the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid-nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening.

Oncolytic viruses (OVs) offer a novel approach to treat solid tumors; however, their efficacy is frequently suboptimal due to various limiting factors. To address this challenge, we engineered an OV containing targets for neuron-specific microRNA-124 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), significantly enhancing its neuronal safety while minimally compromising its replication capacity. Moreover, we identified PARP1 as an HSV-1 replication restriction factor using genome-wide CRISPR screening. In models of glioblastoma (GBM) and triple-negative breast cancer (TNBC), we showed that the combination of OV and a PARP inhibitor (PARPi) exhibited superior efficacy compared to either monotherapy. Additionally, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy sensitized TNBC to immune checkpoint blockade, and the incorporation of an immune checkpoint inhibitor (ICI) further increased the survival rate of tumor-bearing mice. The combination of PARPi and ICI synergistically enhanced the ability of OV to establish durable tumor-specific immune responses. Our study effectively overcomes the inherent limitations of OV therapy, providing valuable insights for the clinical treatment of TNBC, GBM, and other malignancies.

Modified lentiviral globin gene therapy for pediatric ß0/ß0 transfusion-dependent ß-thalassemia: A single-center, single-arm pilot trial.

ß0/ß0 thalassemia is the most severe type of transfusion-dependent ß-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a ß-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in ß0/ß0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5 months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22 months. The treatment extended the lifespan of red blood cells by over 42 days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all ß-thalassemia.

Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Diagnostic performance of angiography-derived fractional flow reserve and CT-derived fractional flow reserve: A systematic review and Bayesian network meta-analysis.

OBJECTIVE: Accumulating evidence has demonstrated that fractional flow reserves (FFRs) derived from invasive coronary angiograms (CA-FFRs) and coronary computed tomography angiography-derived FFRs (CT-FFRs) are promising alternatives to wire-based FFRs. However, it remains unclear which method has better diagnostic performance. This systematic review and meta-analysis aimed to compare the diagnostic performances of the two approaches. METHODS: The Cochrane Library, PubMed, Embase, Medline (Ovid), the Chinese China National Knowledge Infrastructure Database (CNKI), VIP, and WanFang Data databases were searched for relevant studies that included comparisons between CA-FFR and CT-FFR, from their respective database inceptions until January 1, 2023. Studies where both noninvasive FFR (including CA-FFR and CT-FFR) and invasive FFR (as a reference standard) were performed for the diagnosis of ischemic coronary artery disease and were designed as prospective, paired diagnostic studies, were pulled. The diagnostic test accuracy method and Bayesian hierarchical summary receiver operating characteristic (ROC) model for network meta-analysis (NMA) of diagnostic tests (HSROC-NMADT) were both used to perform a meta-analysis on the data. RESULTS: Twenty-six studies were included in this NMA. The results from both the diagnostic test accuracy and HSROC-NMADT methods revealed that the diagnostic accuracy of CA-FFR was higher than that of CT-FFR, in terms of sensitivity (Se; 0.86 vs. 0.84), specificity (Sp; 0.90 vs. 0.78), positive predictive value (PPV; 0.83 vs. 0.70), and negative predictive value (NPV; 0.91 vs. 0.89) for the detection of myocardial ischemia. A cumulative ranking curve analysis indicated that CA-FFR had a higher diagnostic accuracy than CT-FFR in the context of this study, with a higher area under the ROC curve (AUC; 0.94 vs. 0.87). CONCLUSIONS: Although both of these two commonly used virtual FFR methods showed high levels of diagnostic accuracy, we demonstrated that CA-FFR had a better Se, Sp, PPV, NPV, and AUC than CT-FFR. However, this study provided only indirect comparisions; therefore, larger studies are warranted to directly compare the diagnostic performances of these two approaches.

Changes of Facial Lipidomics by Intense Pulsed Light Treatment Based on LC-MS.

BACKGROUND: Intense pulsed light (IPL) has been widely used to improve cutaneous photoaging in recent years. Several studies began to explore the changes of skin barrier function after treatment, but the changes of skin surface lipids (SSL), especially specific lipid content and types are still unclear. METHODS: A total of 25 female volunteers were included in our study, and each of them received three full-face treatments with one month apart. Before the first treatment and 1 month after the last treatment, we collected clinical photos and skin stratum corneum samples from individuals. A 5-level scale was used to evaluate the efficacy of IPL treatment, liquid chromatography-mass spectrometry (LC-MS), and Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA) were used to analyze the changes of SSL. RESULTS: Two patients got no improvement after treatment, 6 patients had poor improvement and mild improvement was achieved in 9 patients, 5 and 3 patients reported moderate and significant improvement. The overall "effective" rate was 68 % and the "significant effective" rate was 32 %. The results showed 18 lipid subclasses and 487 lipid molecules were identified. The change of total lipid volume was not statistically significant (P = 0.088>0.05), but lipid subclass analysis showed the amount of Triglyceride (TG), Phosphatidic Acid (PA), Phosphatidylglycerol (PG) and Lysophosphatidylglycerol (LPG) were significantly increased (P < 0.05). There were 55 kinds of lipid molecules with significant difference after treatment (P < 0.05), and 51 of them belong to TG. The analysis of chain saturation of TG showed that the quantity of TG with 0, 1 and 2 unsaturated bonds increased significantly (P < 0.05). CONCLUSIONS: IPL treatment does not have a significant effect on the overall amount of lipids while the amount of TG, PA, PG, LPG were significantly increased. These lipid changes may potentially improve the skin barrier function, but more high-quality and comprehensive studies are still needed. BULLET POINT: Lipidomics analysis based on LC-MS; Changes of skin surface lipid after IPL treatment; the relationships between skin surface lipid and skin barrier functions. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

In vivo CRISPR gene editing in patients with herpetic stromal keratitis.

In vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of herpes simplex virus 1 (HSV-1)-targeting CRISPR formulation in the cornea of three patients with severe refractory herpetic stromal keratitis (HSK) during corneal transplantation. Our study is an investigator-initiated, open-label, single-arm, non-randomized interventional trial at a single center (NCT04560790). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients. The HSV-1 remained undetectable during the study. Our preliminary clinical results suggest that in vivo gene editing targeting the HSV-1 genome holds acceptable safety as a potential therapy for HSK.

Comparison of Different Chronic Maintenance Antithrombotic Strategies in Patients with Coronary Artery Disease: A Systematic Review and Network Meta-Analysis.

Background: Optimal antithrombotic therapy during the chronic maintenance period in patients with coronary artery disease (CAD) is unknown. We compared five kinds of mainstream chronic maintenance antithrombotic strategies at least one year after the acute phase: aspirin alone, clopidogrel alone, ticagrelor alone, continued dual antiplatelet therapy (DAPT) for a period of time, and maintenance with aspirin combined with a low-dose anticoagulant such as rivaroxaban. Methods: Ten randomized, controlled trials were selected using PubMed, Ovid MEDLINE, Embase, and Cochrane library through February 2023. The primary outcome was main adverse cardiac events (MACEs), and secondary outcomes include net adverse clinical events (NACEs), cardiac death, all-cause death, ischemic stroke, stent thrombosis, total bleeding, and major bleeding. A network meta-analysis was conducted with a random-effects model. Data extraction was performed by three independent reviewers. Results: Our search identified ten eligible randomized controlled trials enrolling a total of 82,084 patients comparing different chronic maintenance antithrombotic strategies. As for the primary endpoint, there was no statistical difference in MACE outcomes between any two of the five methods. As for the secondary endpoint, there was no statistical difference in NACE, major bleeding, all-cause death, cardiac death, and stent thrombosis between any two methods. The aspirin plus low-dose rivaroxaban group had a lower incidence of ischemic stroke compared to the aspirin group (OR = 0.49, 95% CrI 0.26-0.91). And the prolonged DAPT group had a higher total bleeding rate compared to aspirin group (OR = 2.4, 95% CrI 1.1-5.9). Conclusions: In terms of MACE, NACE, all-cause death, cardiac death, stent thrombosis, and major bleeding, there were no significant differences between using aspirin alone, clopidogrel alone, and ticagrelor alone; extending DAPT duration; and using aspirin combined with low-dose rivaroxaban for chronic maintenance antithrombotic regimens. However, choosing aspirin combined with low-dose rivaroxaban can reduce the incidence of ischemic stroke, and prolonged DAPT may have a higher rate of total bleeding. However, it is important to note that this study is based on indirect comparisons, and there is currently a lack of direct evidence comparing various maintenance antiplatelet therapy regimens. Further high-quality studies are needed to address this gap and provide more conclusive evidence on the comparative effectiveness of different maintenance antiplatelet strategies.

Evolutionary mining and functional characterization of TnpB nucleases identify efficient miniature genome editors.

As the evolutionary ancestor of Cas12 nuclease, the transposon (IS200/IS605)-encoded TnpB proteins act as compact RNA-guided DNA endonucleases. To explore their evolutionary diversity and potential as genome editors, we screened TnpBs from 64 annotated IS605 members and identified 25 active in Escherichia coli, of which three are active in human cells. Further characterization of these 25 TnpBs enables prediction of the transposon-associated motif (TAM) and the right-end element RNA (reRNA) directly from genomic sequences. We established a framework for annotating TnpB systems in prokaryotic genomes and applied it to identify 14 additional candidates. Among these, ISAam1 (369 amino acids (aa)) and ISYmu1 (382 aa) TnpBs demonstrated robust editing activity across dozens of genomic loci in human cells. Both RNA-guided genome editors demonstrated similar editing efficiency as SaCas9 (1,053 aa) while being substantially smaller. The enormous diversity of TnpBs holds potential for the discovery of additional valuable genome editors.

Bacterial molecular syringe for drug delivery.

Different protein-delivery tools are being actively developed for efficient drug delivery into host cells. A recent study by Kreitz et al. in Nature reported a syringe-like protein delivery vector engineered from natural endosymbiotic bacteria for potential human use.

Efficacy and safety of intense pulsed light for the treatment of facial erythema: a systematic review and meta-analysis.

INTRODUCTION: Facial erythema can be seen in many patients. Despite various clinical trials exploring the effect of intense pulsed light (IPL) in treating facial erythema, comprehensive evidence about the specific outcomes remains lacking. EVIDENCE ACQUISITION: We searched published studies in the Web of Science, PubMed, Embase, and Cochrane Library databases based on established inclusion criteria. We calculated odds ratios (OR) to evaluate the effectiveness of IPL in patients with facial erythema. We used Review Manager 5.4.1 software for statistical data analyses with a 95% confidence interval (CI). EVIDENCE SYNTHESIS: This review includes seven studies with 219 patients, of which five compared the efficacy of IPL with pulsed dye laser (PDL). IPL significantly improved facial erythema compared to no treatment (OR=56.64, 95% CI: 22.70-141.33; P<0.00001). However, there was no significant difference between IPL and PDL treatment (OR=1.00, 95% CI: 0.31-3.22; P=1.00). Moreover, there was no significant difference in patients with a >50% reduction in telangiectasias between IPL and PDL treatment (OR=1.00, 95% CI: 0.39-2.56; P=1.00). Furthermore, IPL therapy had no apparent adverse effects for most people besides transitory edema and erythema. CONCLUSIONS: Our meta-analysis indicated that IPL could effectively and safely improve facial erythema with similar efficacy to PDL. Based on its comprehensive function, light side effects, and long curative effect, IPL appears to be a good alternative for treating facial erythema. However, further prospective and high-quality studies are required.

Dissolved Solute Sampling Across an Oxic-Anoxic Soil-Water Interface Using Microdialysis Profilers.

Biogeochemical processes shift rapidly in both spatial (millimeter scale) and temporal (hour scale to day scale) dimensions at the oxic-anoxic interface in response to disturbances. Deciphering the rapid biogeochemical changes requires in situ, minimally invasive tools with high spatial and temporal sampling resolution. However, the available passive sampling devices are not very useful in many cases either due to their disposable nature or the complexity and extensive workload for sample preparation. To address this problem, a microdialysis profiler with 33 individual polyethersulfone nanomembrane tubes (semipermeable, <20 nm pore size) integrated into the one-dimensional skeleton (60 mm) was established to iteratively sample the dissolved compounds in porewater across the soil-water interface at a high resolution of 1.8 mm (outer diameter plus one spacing, i.e., 0.1 mm between probes). The sampling mechanism is based on the principle of concentration gradient diffusion. The automatic loading of degassed water allows minimal disturbance to the chemical species across the oxic-anoxic interface. This paper describes the procedures of device setup and continuous porewater sampling across the soil-water interface on a daily basis. Concentration-depth profiles were selectively measured before (on Day 6) and after (on Day 7) disturbances induced by irrigation. The results showed that concentration-depth profiles were undergoing rapid changes, especially for redox-sensitive elements (i.e., iron and arsenic). These protocols can help investigate the biogeochemical responses across the soil-water interface under various disturbances caused by physical, chemical, and biological factors. The paper thoroughly discusses the advantages and disadvantages of this method for potential use in the environmental sciences.

Exploring the mechanism of Xiaoqinglong decoction in the treatment of infantile asthma based on network pharmacology and molecular docking.

To explore the mechanism of Xiaoqinglong decoction (XQLD) in the treatment of infantile asthma (IA) based on network pharmacology and molecular docking. The active ingredients of fdrugs in XQLD were retrieved from Traditional Chinese Medicine Systems Pharmacology database and then the targets of drug ingredients were screened. The disease targets of IA were obtained from OMIM and Gencards databases, and the intersection targets of XQLD in the treatment of IA were obtained by Venny 2.1 mapping of ingredient targets and disease targets. Cytoscape software was used to construct active ingredient-intersection target network. The potential targets of XQLD in the treatment of IA were analyzed by protein-protein interaction network using STRING platform, and the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were obtained by R Studio software. AutoDock was used to perform molecular docking for verification. In this study, 150 active ingredients of XQLD were obtained, including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and so on. And 92 intersection targets of drugs and diseases were obtained, including interleukin 6 (IL6), cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, epidermal growth factor receptor and so on. There were 127 items of Gene Ontology enrichment analysis and 125 Kyoto Encyclopedia of Genes and Genomes enrichment results, showing that apoptosis, IL-17 signaling pathway, tumor necrosis factor signaling pathway, P13K-Akt signaling pathway and other pathways may play a key role in the treatment of IA by XQLD. The results of molecular docking showed that the key active ingredients including quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol, and the core targets including IL6, cystatin 3, estrogen receptor 1, hypoxia inducible factor 1A, HSP90AA1, and epidermal growth factor receptor had good binding activity. Through network pharmacology and molecular docking, the potential targets and modern biological mechanisms of XQLD in the treatment of IA were preliminarily revealed in the study, which will provide reference for subsequent animal experiments and clinical trials.

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway.

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.

The Efficacy of Fractional Carbon Dioxide Laser in Surgical Scars Treatment: A system Review and Meta-analysis.

BACKGROUND: Surgical scars seriously affect a patient's quality of life, and they have a strong impact on individuals. Many studies have reported the results of using fractional carbon dioxide (CO2) laser to treat surgical scars and have generally found it to be effective. OBJECTIVES: We conducted a meta-analysis with the objective of evaluating and proving the efficacy of fractional CO2 laser therapy for surgical scars. METHODS: We performed a search of databases including PubMed, Web of Science, Embase and the Cochrane Library. The outcomes of the meta-analysis were overall scores on the Vancouver Scar Scale (VSS) and its four dimensions (pigmentation, vascularity, pliability and height). Statistical analysis was performed using RevMan 5.4 software. RESULTS: A total of ten studies were included in this meta-analysis, including six randomized controlled trials (RCTs) and four nonrandomized controlled trials (N-RCTs). In the meta-analysis of RCTs and N-RCTs, similar results were obtained, and fractional CO2 laser irradiation significantly decreased VSS scores (P < 0.00001). In addition, fractional CO2 laser irradiation also had a significant effect on scores on the pigmentation (P = 0.08), vascularity (P = 0.001), flexibility (P = 0.005) and height (P = 0.008) dimensions. Except for mild pain during treatment and temporary erythema after treatment, most patients had no obvious adverse reactions. CONCLUSION: Our study found that fractional CO2 laser exhibits excellent efficacy and safety in terms of surgical scar treatment. Thus, we hope it becomes more widely available to patients with surgical scars. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Buprenorphine reduces methamphetamine intake and drug seeking behavior via activating nociceptin/orphanin FQ peptide receptor in rats.

Buprenorphine, which has been approved for the treatment of opioid dependence, reduces cocaine consumption by co-activating µ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. However, the role of buprenorphine in methamphetamine (METH) reinforcement and drug-seeking behavior remains unclear. This study investigated the effects of buprenorphine on METH self-administration and reinstatement of METH-seeking behavior in rats. We found that buprenorphine pretreatment had an inhibitory effect on METH self-administration behavior, and that buprenorphine at a dose of 0.3 mg/kg could inhibit motivation to respond for METH. Pretreatment with the NOP receptor antagonist thienorphine (0.5 mg/kg) or SB-612111 (1 mg/kg) could reverse the inhibitory effect of buprenorphine (0.1 mg/kg) on the METH self-administration. Moreover, treatment with buprenorphine (0.1 mg/kg and 0.3 mg/kg) significantly reduced the drug-seeking behavior induced by context or by METH priming but failed to reduce the drug-seeking behavior induced by conditional cues. Additionally, the NOP receptor antagonist SB-612111 reversed the inhibitory action of buprenorphine on the drug-seeking behavior induced by METH priming. The results demonstrated that buprenorphine reduced either METH intake or the drug-seeking behavior by activating NOP receptors, providing empirical evidence for the clinical use of buprenorphine in the treatment of METH relapse and addiction.

Intense pulsed light treatment for inflammatory skin diseases: a review.

Although intense pulsed light (IPL) has been commonly used in the field of medical cosmetics in recent years, the exact outcomes of IPL in the treatment of inflammatory skin diseases remain unclear. To assess the clinical evidence for the use of IPL in the treatment of various inflammatory skin diseases and propose evidence-based recommendations, we searched for relevant publications in the PubMed and Web of Science databases and provided updated information. The inflammatory skin diseases treated with IPL consisted of acne vulgaris, rosacea, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), Riehl's melanosis, lupus erythematosus, cutaneous sarcoidosis, pilonidal cysts, and pigmented actinic lichen planus (PALP). The efficacy of IPL treatment for these inflammatory skin diseases was described and evaluated. Forty-two studies were included to provide this assessment. The evidence suggests that IPL can effectively and safely improve acne vulgaris and rosacea (recommendation grade B). For other described inflammatory skin diseases, IPL can be used as a tentative or supplementary treatment (recommendation grade C and D). The main complications include transitory erythema, edema, and pain, with the possibility of hyperpigmentation, blisters, and a burning sensation in some individuals.

Frameshift and wild-type proteins are often highly similar because the genetic code and genomes were optimized for frameshift tolerance.

Frameshift mutations have been considered of significant importance for the molecular evolution of proteins and their coding genes, while frameshift protein sequences encoded in the alternative reading frames of coding genes have been considered to be meaningless. However, functional frameshifts have been found widely existing. It was puzzling how a frameshift protein kept its structure and functionality while substantial changes occurred in its primary amino-acid sequence. This study shows that the similarities among frameshifts and wild types are higher than random similarities and are determined at different levels. Frameshift substitutions are more conservative than random substitutions in the standard genetic code (SGC). The frameshift substitutions score of SGC ranks in the top 2.0-3.5% of alternative genetic codes, showing that SGC is nearly optimal for frameshift tolerance. In many genes and certain genomes, frameshift-resistant codons and codon pairs appear more frequently than expected, suggesting that frameshift tolerance is achieved through not only the optimality of the genetic code but, more importantly, the further optimization of a specific gene or genome through the usages of codons/codon pairs, which sheds light on the role of frameshift mutations in molecular and genomic evolution.

An extension of the RIGHT statement for introductions and interpretations of clinical practice guidelines: RIGHT for INT.

OBJECTIVE: The purpose of the extension of the RIGHT Statement for INTroductions and INTerpretations of Clinical Practice Guidelines (RIGHT for INT) is to promote the development of comprehensive and clear articles that introduce and interpret clinical practice guidelines. METHODS: The RIGHT for INT checklist was developed following methods recommended by the EQUATOR Network. The development process included three stages. In the first stage, a multidisciplinary team of experts was recruited by email and WeChat and further divided into three groups (a steering group, a consensus group, and a secretariat group); in the second stage, the initial items were collected by literature review and brainstorming; and in the third stage, the final items were formed through a Delphi survey and expert consultation. RESULTS: A total of 40 initial items were collected through literature review and brainstorming. A final checklist of 27 items was formed after the Delphi survey and expert consultation. The RIGHT for INT checklist contains items on the following 10 topics: title, abstract, background of guideline interpretation, background of guideline development, guideline development methodology, recommendations, strengths, and limitations, implications for local guidelines and clinical research, dissemination and implementation, and reporting quality. CONCLUSION: The RIGHT for INT checklist provides guidance for guideline interpreters on how to introduce and interpret clinical practice guidelines in a scientific and comprehensive manner.