An interaction between eIF4A3 and eIF3g drives the internal initiation of translation.

An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as ß-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.

Enhancement of the signal-to-noise ratio in fiber-optics based SERS detection by rough-cutting the end surface.

Fiber-optics based surface-enhanced Raman scattering (FO-SERS) has an unique advantage of being able to remotely detect analyte molecules because the fiber length can be adjusted as desired. However, the Raman signal of the fiber-optic material is so strong that it is an important challenge in utilization of optical fiber for remote SERS sensing. In this study, we found that the background noise signal was greatly reduced by ca. 32% compared to conventional fiber-optics with a flat surface cut. To confirm the feasibility of FO-SERS detection, silver nanoparticles labeled with 4-fluorobenzenethiol were attached onto the end surface of an optical fiber to form a SERS-signaling substrate. The SERS intensity from the fiber-optics with a roughened surface as SERS substrate was increased significantly with respect to signal-to-noise ratio (SNR) values compared to optical fibers with flat end surface. This result implies that the fiber-optics with roughened surface could be used as an efficient alternative for FO-SERS sensing platform.

CUSUM learning curves: what they can and can't tell us.

INTRODUCTION: There has been increased interest in assessing the surgeon learning curve for new skill acquisition. While there is no consensus around the best methodology, one of the most frequently used learning curve assessments in the surgical literature is the cumulative sum curve (CUSUM) of operative time. To demonstrate the limitations of this methodology, we assessed the CUSUM of console time across cohorts of surgeons with differing case acquisition rates while varying the total number of cases used to calculate the CUSUM. METHODS: We compared the CUSUM curves of the average console times of surgeons who completed their first 20 robotic-assisted (RAS) cases in 13, 26, 39, and 52 weeks, respectively, for their first 50 and 100 cases, respectively. This analysis was performed for prostatectomy (1094 surgeons), malignant hysterectomy (737 surgeons), and inguinal hernia (1486 surgeons). RESULTS: In all procedures, the CUSUM curve of the cohort of surgeons who completed their first 20 procedures in 13 weeks demonstrated a lower slope than cohorts of surgeons with slower case acquisition rates. The case number at which the peak of the CUSUM curve occurs uniformly increases when the total number of cases used in generation of the CUSUM chart changes from 50 to 100 cases. CONCLUSION: The CUSUM analyses of these three procedures suggests that surgeons with fast initial case acquisition rates have less variability in their operative times over the course of their learning curve. The peak of the CUSUM curve, which is often used in surgical learning curve literature to denote "proficiency" is predictably influenced by the total number of procedures evaluated, suggesting that defining the peak as the point at which a surgeon has overcome the learning curve is subject to routine bias. The CUSUM peak, by itself, is an insufficient measure of "conquering the learning curve."

Utility of illness symptoms for predicting COVID-19 infections in children.

BACKGROUND: The Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend that symptomatic children remain home and get tested to identify potential coronavirus disease 2019 (COVID-19) cases. As the pandemic moves into a new phase, approaches to differentiate symptoms of COVID-19 versus other childhood infections can inform exclusion policies and potentially prevent future unnecessary missed school days. METHODS: Retrospective analysis of standardized symptom and exposure screens in symptomatic children 0-18 years tested for SARS-CoV-2 at three outpatient sites April to November 2020. Likelihood ratios (LR), number needed to screen to identify one COVID-19 case, and estimated missed school days were calculated. RESULTS: Of children studied (N = 2,167), 88.9% tested negative. Self-reported exposure to COVID-19 was the only factor that statistically significantly increased the likelihood of a positive test for all ages (Positive LR, 5-18 year olds: 5.26, 95% confidence interval (CI): 4.37-6.33; 0-4 year olds: 5.87, 95% CI: 4.67-7.38). Across ages 0-18, nasal congestion/rhinorrhea, sore throat, abdominal pain, and nausea/vomiting/diarrhea were commonly reported, and were either not associated or had decreased association with testing positive for COVID-19. The number of school days missed to identify one case of COVID-19 ranged from 19 to 48 across those common symptoms. CONCLUSIONS: We present an approach for identifying symptoms that are non-specific to COVID-19, for which exclusion would likely lead to limited impact on school safety but contribute to school-days missed. As variants and symptoms evolve, students and schools could benefit from reconsideration of exclusion and testing policies for non-specific symptoms, while maintaining testing for those who were exposed.

Oligomers of α-ABpeptoid/ß3 -peptide hybrid.

Peptoids, oligomers of N-substituted glycines, have been attracting increasing interest due to their advantageous properties as peptidomimetics. However, due to the lack of chiral centers and amide hydrogen atoms, peptoids, in general, do not form folding structures except that they have α-chiral side chains. We have recently developed "peptoids with backbone chirality" as a new class of peptoid foldamers called α-ABpeptoids and demonstrated that they could have folding conformations owing to the methyl groups on chiral α-carbons in the backbone structure. Here we report α-ABpeptoid/ß3 -peptide oligomers as a unique peptidomimetic structure with a heterogeneous backbone. This hybrid structure contains a mixed α-ABpeptoid and ß3 -peptide residues arranged in an alternate manner. These α-ABpeptoid/ß3 -peptide oligomers could form intramolecular hydrogen bonding and have better cell permeability relative to pure peptide sequences. These oligomers were shown to adopt ordered folding structures based on circular dichroism studies. Overall, α-ABpeptoid/ß3 -peptide oligomers may represent a novel class of peptidomimetic foldamers and will find a wide range of applications in biomedical and material sciences.

Utility of allogeneic hematopoietic stem cell transplantation using international donors in a homogenous ethnic population: question in the era of various alternative donors.

The advent of various alternative donors in allogeneic hematopoietic stem cell transplantation (HSCT) raises the question of using international donors, especially in ethnically homogenous populations. We analyzed the clinical outcome and medical expense of human leukocyte antigen (HLA)-matched HSCT using domestic and international donors. We analyzed the patients who received allogeneic HSCT at five medical centers in Korea in the last 10 years. Using propensity-score matching, we compared overall survival (OS), relapse-free survival (RFS), and transplantation-related complications. Medical expense was analyzed based on National Health Insurance Service (NHIS) data. A total of 269 patients were analyzed after 3:1 (domestic/international) matching. There was no difference in OS (p = 0.395) and RFS (p = 0.604) between the domestic and international donor groups (5-year OS rate 42.9 and 37.8%, 5-year RFS rate 37.6 and 33.5% for domestic and international groups, respectively). No difference in chronic graft-versus-host disease (GVHD) incidence was observed (34.2% in domestic and 35.9% in international group, p = 0.804). Early infection was more frequent in the domestic group (55.0 vs. 35.8%, p = 0.007), whereas infection after 30 days was more frequent in the international group (28.7 vs. 49.3%, p = 0.001). Mean medical expense was far higher in the international group, by US $51,944 in the entire follow-up period (p < 0.001). We would expect similar outcomes for international and domestic donors in terms of survival and treatment-related complications with HLA-matched HSCT in other ethnically homogenous populations. These findings should be considered together with the high cost of using international donors in the era of various alternative donors.

Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.

The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.

Amygdaloid and non-amygdaloid fear both influence avoidance of risky foraging in hungry rats.

Considerable evidence seems to show that emotional and reflex reactions to feared situations are mediated by the amygdala. It might therefore seem plausible to expect that amygdala-coded fear should also influence decisions when animals make choices about instrumental actions. However, there is not good evidence of this. In particular, it appears, though the literature is conflicted, that once learning is complete, the amygdala may often not be involved in instrumental avoidance behaviours. It is therefore of interest that we have found in rats living for extended periods in a semi-naturalistic 'closed economy', where they were given random shocks in regions that had to be entered to obtain food, choices about feeding behaviour were in fact influenced by amygdala-coded fear, in spite of the null effect of amygdalar lesions on fear of dangerous location per se. We suggest that avoidance of highly motivated voluntary behaviour does depend in part on fear signals originating in the amygdala. Such signalling may be one role of well-known projections from amygdala to cortico-striate circuitry.

Histologic comparison of microscopic treatment zones induced by fractional lasers and radiofrequency.

INTRODUCTION: Fractional photothermolysis induces microscopic, localized thermal injury in the skin surrounded by undamaged viable tissue in order to promote wound healing. OBJECTIVE: This study evaluated acute histologic changes following each single pass of various fractional lasers and radiofrequency (RF). METHODS: Three male domestic swine were used. We used fractional Erbium:glass (Er:glass), Erbium:yttrium-aluminum-garnet (Er:YAG), CO2 lasers, and fractional ablative microplasma RF. We analyzed features and average values of the diameter, depth, and vertical sectional areas treated with each kind of laser and RF. RESULTS: The microscopic treatment zone (MTZ) of fractional Er:glass resulted in separation of dermoepidermal junction with no ablative zone. Fractional Er:YAG provided the most superficial and broad MTZ with little thermal collateral damage. Fractional CO2 resulted in a narrow and deep "cone"-like MTZ. Fractional RF resulted in a superficial and broad "crater"-like MTZ. CONCLUSIONS: This study provides the first comparison of MTZs induced by various fractional lasers and RF. These data provide basic information on proper laser and RF options. We think that these findings could be a good reference for information about fractional laser-assisted drug delivery.

Brain Sample Preparation After Performing in Utero Electroporation to Proliferating and Differentiated Cells in the Developing Mouse Neocortex.

In utero electroporation (IUE) enables labeling and manipulating specific types of cells by introducing DNA plasmids with desired promoters. After the surgery, mouse brains are fixed at any stage and analyzed after staining using specific antibodies. Here, we describe the flow of the IUE experiment from the preparation to microscopic observations.

Nonsense-mediated mRNA decay of mRNAs encoding a signal peptide occurs primarily after mRNA targeting to the endoplasmic reticulum.

Translation of messenger ribonucleic acids (mRNAs) encoding integral membrane proteins or secreted proteins occurs on the surface of the endoplasmic reticulum (ER). When a nascent signal peptide is synthesized from the mRNAs, the ribosome-nascent chain complex (RNC) is recognized by the signal recognition particle (SRP) and then transported to the surface of the ER. The appropriate targeting of the RNC-SRP complex to the ER is monitored by a quality control pathway, a nuclear cap-binding complex (CBC)-ensured translational repression of RNC-SRP (CENTRE). In this study, using ribosome profiling of CBC-associated and eukaryotic translation initiation factor 4E-associated mRNAs, we reveal that, at the transcriptomic level, CENTRE is in charge of the translational repression of the CBC-RNC-SRP until the complex is specifically transported to the ER. We also find that CENTRE inhibits the nonsense-mediated mRNA decay (NMD) of mRNAs within the CBC-RNC-SRP. The NMD occurs only after the CBC-RNC-SRP is targeted to the ER and after eukaryotic translation initiation factor 4E replaces CBC. Our data indicate dual surveillance for properly targeting mRNAs encoding integral membrane or secretory proteins to the ER. CENTRE blocks gene expression at the translation level before the CBC-RNC-SRP delivery to the ER, and NMD monitors mRNA quality after its delivery to the ER.

Physical Properties of Paste Synthesized from Wet- and Dry-Processed Silver Powders.

This study compares the characteristics and low-temperature curing properties of pastes prepared from silver (Ag) powders synthesized by either wet powder (WP) or dry powder (DP) processing. The WP synthesis of electrode particles has the advantage of controlling the average particle size and particle size distribution but the disadvantage of producing low-purity, crystalline particles because they are synthesized through chemical reduction at less than 100 °C. Conversely, the DP synthesis of electrode particles has the advantage of producing pure, highly crystalline particles (due to synthesis at high temperatures) but the disadvantage of a high processing cost. WP and DP were used to manufacture pastes for low-temperature curing, and the physical properties of the pastes and the electrode characteristics after low-temperature curing were compared between powder types. Shear stress as a function of the shear rate shows that the WP paste is a plastic fluid, whereas the DP paste is a pseudoplastic fluid, closer to a Newtonian fluid. Screen printing the Ag pastes and curing for 30 min at 130 °C produces a nonconductive WP paste, whereas it produces a DP paste with a conductivity of 61 mΩ/sq, indicating that the highly crystalline DP paste is advantageous for low-temperature curing.

Review of epilepsy care in the Democratic Republic of the Congo.

Epilepsy imposes a substantial burden on the Democratic Republic of Congo (DRC). These challenges encompass the lack of comprehensive disease surveillance, an unresolved understanding of its pathophysiology, economic barriers limiting access to essential care, the absence of epilepsy surgical capabilities, and deeply ingrained societal stigmas. Notably, the national prevalence of epilepsy remains undetermined, with research primarily concentrating on infectious factors like Onchocerca volvulus, leaving other potential causes underexplored. Most patients lack insurance, incurring out-of-pocket expenses that often lead them to opt for traditional medicine rather than clinical care. Social stigma, perpetuated by common misconceptions, intensifies the social isolation experienced by individuals living with epilepsy. Additionally, surgical interventions are unavailable, and the accessibility of anti-seizure medications and healthcare infrastructure remains inadequate. Effectively tackling these interrelated challenges requires a multifaceted approach, including conducting research into region-specific factors contributing to epilepsy, increasing healthcare funding, subsidizing the costs of treatment, deploying mobile tools for extensive screening, launching awareness campaigns to dispel myths and reduce stigma, and promoting collaborations between traditional healers and medical practitioners to enhance local understanding and epilepsy management. Despite the difficulties, significant progress can be achieved through sustained and compassionate efforts to understand and eliminate the barriers faced by epilepsy patients in the region. This review outlines essential steps for alleviating the epilepsy burden in the DRC. PLAIN LANGUAGE SUMMARY: There are not enough resources to treat epilepsy in the DRC. PWEs struggle with stigma and the lack of money. Many of them still use traditional medicine for treatment and hold wrong beliefs about epilepsy. That is why there is a need for more resources to make the lives of PWEs better in the DRC.

Analysis of the temporal change in biophysical parameters after fractional laser treatments using reflectance confocal microscopy.

BACKGROUND: Fractional photothermolysis is a popular treatment option for photorejuvenation. Previous literature studies have demonstrated the clinical effectiveness of fractional photothermolysis on cutaneous photoaging; however, the associated changes in biophysical properties of the skin following fractional photothermolysis have not been fully elucidated. This study was conducted to investigate the temporal changes in biophysical parameters after fractional laser treatment on Asian skin. MATERIALS AND METHODS: Eleven female subjects underwent a single treatment with an erbium glass fractional laser. Skin roughness, elasticity, transepidermal water loss (TEWL), dermal thickness were evaluated before and immediately after treatment and 3 days, 1 week, 2 weeks, and 4 weeks after treatment. The changes in the dermal papilla were analyzed using a reflectance confocal microscopy (RCM). RESULTS: Skin roughness showed the greatest improvement at the first week and net elasticity was most improved at the second week. TEWL and the percentage of melanized and active dermal papillae (DP) were mostly increased for 3 days. At 4 weeks after treatment, the number of total dermal papillae showed a significant increase compared with pretreatment. CONCLUSION: This is the first study of the characterization and quantification of dermal papilla reflecting the dermal repair process after fractional photothermolysis through an RCM.

Bullous eosinophilic cellulitis in a child treated with dapsone.

Eosinophilic cellulitis, or Wells syndrome, is a rare but well-described condition in which bullous lesions are uncommon, especially in childhood. We report a case of bullous eosinophilic cellulitis recalcitrant to steroid therapy in a 9-year-old boy who was successfully treated with oral dapsone.

Inhibitory effect of Gastrodia elata extract on melanogenesis in HM3KO melanoma cells.

Effective and safe antimelanogenic agents derived from natural products get interest continuously for both medical and cosmetic purposes. Melanin synthesis is regulated by melanogenic enzymes such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2) in mammals. Gastrodia elata (GE) has been shown to have multiple therapeutic actions related to antioxidation in many diseases. In this study, we investigate whether water extraction of GE has inhibitory effects on melanogenesis in vitro and on the expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 in HM3KO melanoma cells. To examine the inhibitory effect of GE on melanogenesis, mushroom tyrosinase inhibition assay; reverse transcription polymerase chain reaction; and western blotting of tyrosinase, TRP-1, and TRP-2 were performed using HM3KO melanoma cells. In this study, the GE extract was found to significantly inhibit mushroom tyrosinase activity (69.3 ± 7.2% of the control, p < 0.05), and the expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 was reduced significantly. These results suggest that the antimelanogenic effect of GE extract is mainly due to the decreased expression of mRNA and protein of tyrosinase, TRP-1, and TRP-2 in the process of melanin synthesis.

Demographic and Clinical Factors Affecting Pediatric Survival in South Kivu, the Democratic Republic of the Congo.

Promoting children's health is challenging in underresourced regions, with worse outcomes in areas of sociopolitical instabilities. This encapsulates the difficulties faced by the Panzi General Referral Hospital (PGRH) in South Kivu, the Democratic Republic of the Congo. In this retrospective, cross-sectional study of 456 children ≤ 18 years who presented to the pediatric emergency department of PGRH between December 2018 and May 2019, we present demographic and clinical predictors that affect pediatric survival. We note that referrals from external clinics (odds ratio [OR], 0.37; 95% CI, 0.18-0.75), poor maternal education (OR, 0.21; 95% CI, 0.07-0.67), diagnoses of meningitis (OR, 0.37; 95% CI, 0.18-0.75) or malnutrition (OR, 0.21; 95% CI, 0.07-0.67) are risk factors hindering pediatric survival. Paternal unemployment or longer durations of hospital stay, on the other hand, are protective toward survival. These predictors confirm the importance of accessibility and availability of medical resources and knowledge as levers to establish an effective, robust network of pediatric care delivery capable of withstanding South Kivu's unresolved political tumult.

Lamin B1 as a key modulator of the developing and aging brain.

Lamin B1 is an essential protein of the nuclear lamina that plays a crucial role in nuclear function and organization. It has been demonstrated that lamin B1 is essential for organogenesis and particularly brain development. The important role of lamin B1 in physiological brain development and aging has only recently been at the epicenter of attention and is yet to be fully elucidated. Regarding the development of brain, glial cells that have long been considered as supporting cells to neurons have overturned this representation and current findings have displayed their active roles in neurogenesis and cerebral development. Although lamin B1 has increased levels during the differentiation of the brain cells, during aging these levels drop leading to senescent phenotypes and inciting neurodegenerative disorders such as Alzheimer's and Parkinson's disease. On the other hand, overexpression of lamin B1 leads to the adult-onset neurodegenerative disease known as Autosomal Dominant Leukodystrophy. This review aims at highlighting the importance of balancing lamin B1 levels in glial cells and neurons from brain development to aging.

Platelet-rich plasma combined with fractional laser therapy for skin rejuvenation.

BACKGROUND AND OBJECTIVES: Platelet-rich plasma (PRP) is an autologous concentration of human platelets contained in a small volume of plasma and has recently been shown to accelerate wound healing and rejuvenate aging skin. The current study was conducted to determine whether there are additional effects of PRP combined with fractional laser therapy. MATERIALS AND METHODS: Twenty-two Korean women underwent three sessions of fractional laser; 11 were treated with topical application of PRP combined with fractional laser. Evaluations were done at baseline and 1 month after the final treatment. The outcome assessments included subjective satisfaction scale; blinded clinical assessment; and the biophysical parameters of roughness, elasticity, skin hydration, and the erythema and melanin index. Biopsies were analyzed using hematoxylin and eosin, Masson-trichrome, and immunohistochemistry for matrix metalloproteinase-1. RESULTS: PRP combined with fractional laser increased subject satisfaction and skin elasticity and decreased the erythema index. PRP increased the length of the dermoepidermal junction, the amount of collagen, and the number of fibroblasts. CONCLUSION: PRP with fractional laser treatment is a good combination therapy for skin rejuvenation. Keratinocyte and fibroblast proliferation and collagen production can explain the capacity of PRP to increase dermal elasticity.

A intense-focused ultrasound tightening for the treatment of infraorbital laxity.

BACKGROUND: Infraorbital laxity is a common problem that increases with age. Blepharoplasty with lipectomy is a very commonly performed surgical procedure to treat this problem; however, it is invasive and is associated with the potential for re-emergence. Therefore, young patients may prefer a non-surgical procedure rather than to a surgical procedure. Intense-focused ultrasound (IFUS) has emerged as an effective, non-surgical, tissue-tightening procedure. OBJECTIVE: This study assessed the safety and efficacy of IFUS (Ulthera system, Ulthera Inc, Mesa, AZ, U.S.A.) for facial tightening in Asian patients with infraorbital laxity. METHODS: We studied 15 patients who were treated with an IFUS device applied to both lower eyelids. The primary outcome measure was an objective improvement in a paired comparison of pre-treatment and post treatment (6 months) photographs. A secondary outcome measure was patient satisfaction as measured by a questionnaire. RESULTS: The mean patient age was 50 years (range, 27-69). All patients received one to two treatments with intense-focused ultrasound. All patients in the study experienced both subjective and objective improvement. CONCLUSION: IFUS can be used as a non-invasive, skin-tightening procedure for infraorbital laxity. No serious, permanent, or delayed side effects were noted up to 6 months post treatment. Thus, this procedure can be effective and safe in the treatment of decreased laxity of the lower eyelids.