Prevalence of overweight and obesity, dietary behaviors, and physical activities among sixth graders: a cross-sectional study in Ho Chi Minh City, Vietnam.

The prevalence of overweight and obesity among adolescents has been increasing worldwide and is a significant public health challenge. Obesity is linked to several non-communicable diseases. This study aimed to determine the prevalence of overweight and obesity based on three growth references and described physical activities and dietary patterns among sixth graders in Ho Chi Minh City (HCMC). From 2018 to 2020, a cross-sectional study was conducted on 1375 students from 16 junior high schools in HCMC. We applied Probability Proportional to Size sampling to select schools. Anthropometric measurements, pubertal status assessment, and diet and physical activity data were collected through Food Frequency and Physical Activity Questionnaires. The study revealed a high prevalence of overweight and obesity among grade 6 students, with ∼45%-56% of students classified as overweight or obese using various growth references. Moreover, most students did not meet the World Health Organization's physical activity and sedentary behavior recommendations. Most students spent <60 min/day on moderate to vigorous physical activity, and over 70% spent at least 120 min/day on sedentary activities during weekdays and weekends. The diet of the students was also imbalanced, with high intakes of protein, lipids, and carbohydrates and low consumption of fruits and vegetables. Nutritionists and policymakers should inform and encourage opportunities for healthier food and more daily activity for children, starting before the sixth-grade, so they can learn how to make healthier choices and change their behavior before they reach adolescence.

Evaluation of the diagnostic sensitivity and specificity of two pen-side tests for detecting African swine fever virus in experimentally infected pigs.

African swine fever virus (ASFV) has spread through many countries and regions worldwide, causing significant losses. Timely detection of ASFV-infected pigs is crucial for disease control. In this study, we assessed the performance of two pen-side tests: a portable real-time PCR (qPCR) test for detecting viral genomic DNA and a lateral flow immunoassay (LFIA) for detecting viral antigens. To determine the time from infection to the earliest detection, 10 ASFV-seronegative pigs were inoculated intramuscularly with 104.0 hemadsorption dose 50 of a highly virulent ASFV strain. Whole blood and oral swab samples were alternately collected from each group of five pigs daily until all succumbed to the infection. Samples were promptly subjected to the two pen-side tests upon collection, and a subset was transported to a veterinary diagnostic laboratory for analysis using a reference qPCR assay. Viral genomic DNA was consistently detected by the reference qPCR assay in all blood samples from 2 days postinfection (dpi), preceding the onset of clinical signs, and in oral swabs from 4 dpi onwards. The portable qPCR test demonstrated comparable performance to the reference qPCR assay for both whole blood and oral swab samples. The LFIA exhibited 100% specificity when testing with whole blood samples but showed reduced sensitivity, particularly for blood samples collected early or late after infection. The antigen test did not perform well with oral swabs.

Ultrasonic mapping of midpalatal suture - An ex-vivo study.

OBJECTIVE: Rapid maxillary expansion is a common orthodontic procedure to correct maxillary constriction. Assessing the midpalatal suture (MPS) expansion plays a crucial role in treatment planning to determine its effectiveness. The objectives of this preliminary investigation are to demonstrate a proof of concept that the palatal bone underlying the rugae can be clearly imaged by ultrasound (US) and the reconstructed axial view of the US image accurately maps the MPS patency. METHODS: An ex-vivo US scanning was conducted on the upper jawbones of two piglet's carcasses before and after the creation of bone defects, which simulated the suture opening. The planar images were processed to enhance bone intensity distribution before being orderly stacked to fuse into a volume. Graph-cut segmentation was applied to delineate the palatal bone to generate a bone volume. The accuracy of the reconstructed bone volume and the suture opening was validated by the micro-computed tomography (µCT) data used as the ground truth and compared with cone beam computed tomography (CBCT) data as the clinical standard. Also included in the comparison is the rugae thickness. Correlation and Bland-Altman plots were used to test the agreement between the two methods: US versus µCT/CBCT. RESULTS: The reconstruction of the US palatal bone volumes was accurate based on surface topography comparison with a mean error of 0.19 mm for pre-defect and 0.15 mm and 0.09 mm for post-defect models of the two samples, respectively when compared with µCT volumes. A strong correlation (R2 ≥ 0.99) in measuring MPS expansion was found between US and µCT/CBCT with MADs of less than 0.05 mm, 0.11 mm and 0.23 mm for US, µCT and CBCT, respectively. CONCLUSIONS: It was possible to axially image the MPS opening and rugae thickness accurately using high-frequency ultrasound. CLINICAL SIGNIFICANCE: This study introduces an ionizing radiation-free, low-cost, and portable technique to accurately image a difficult part of oral cavity anatomy. The advantages of conceivable visualization could promise a successful clinical examination of MPS to support the predictable treatment outcome of maxillary transverse deficiency.

Facile synthesis of gold nanostars for the duplex detection of pesticide residues in grapes using SERS.

In recent years, concerns have been raised regarding the contamination of grapes with pesticide residues. As consumer demand for safer food products grows, regular monitoring of pesticide residues in food has become essential. This study sought to develop a rapid and sensitive technique for detecting two specific pesticides (phosmet and paraquat) present on the grape surface using the surface-enhanced Raman spectroscopy (SERS) method. Gold nanostars (AuNS) particles were synthesized, featuring spiky tips that act as hot spots for localized surface plasmon resonance, thereby enhancing Raman signals. Additionally, the roughened surface of AuNS increases the surface area, resulting in improved interactions between the substrate and analyte molecules. Prominent Raman peaks of mixed contaminants were acquired and used to characterize and quantify the pesticides. It was observed that the SERS intensity of the Raman peaks changed in proportion to the concentration ratio of phosmet and paraquat. Moreover, AuNS exhibited superior SERS enhancement compared to gold nanoparticles. The results demonstrate that the lowest detectable concentration for both pesticides on grape surfaces is 0.5 mg/kg. These findings suggest that SERS coupled with AuNS constitutes a practical and promising approach for detecting and quantifying trace contaminants in food. PRACTICAL APPLICATION: This research established a novel surface-enhanced Raman spectroscopy (SERS) method coupled with a simplified extraction protocol and gold nanostar substrates to detect trace levels of pesticides in fresh produce. The detection limits meet the maximum residue limits set by the EPA. This substrate has great potential for rapid measurements of chemical contaminants in foods.

Targeted multiparametric magnetic resonance imaging/transrectal ultrasound-guided (mpMRI/TRUS) fusion prostate biopsy versus systematic random prostate biopsy: A comparative real-life study.

BACKGROUND: Patients with suspected prostate cancer usually undergo transrectal ultrasound-guided (TRUS) systematic biopsy, which can miss relevant prostate cancers and lead to overtreatment. AIMS: The aim of this study was to evaluate the detection rate for prostate cancer in MR-guided targeted biopsy (TB) and systematic biopsy (SB) in comparison with mpMRI of the prostate. METHODS AND RESULTS: Three hundred and eight men who underwent mpMRI due to elevated PSA values between 2015 and 2020 were studied at university hospital Aachen, Germany. MRI-images were divided into cohorts with suspicious findings (PI-RADS ≥ 3) and negative findings (PI-RADS < 3). In patients with PI-RADS ≥ 3 TB combined with SB was performed. A part of this group underwent RP subsequently. In patients with PI-RADS < 3 and clinical suspicion SB was performed. In the PI-RADS ≥ 3 group (n = 197), TB combined with SB was performed in 194 cases. Three cases were lost to follow-up. Biopsy yielded 143 positive biopsies and 51 cases without carcinoma. TB detected 71% (102/143) and SB 98% (140/143) of the overall 143 carcinoma. Overall, 102 carcinomas were detected by TB, hereof 66% (67/102) clinically significant (Gleason ≥ 3+4) and 34% (35/102) clinically insignificant carcinoma (Gleason 3+3). SB detected 140 carcinomas, hereof 64% (90/140) csPCA and 36% (50/140) nsPCA. Forty-one of the overall 143 detected carcinoma were only found by SB, hereof 46% (19/41) csPCA and 54% (22/41) nsPCA. Tumor locations overlapped in 44% (63/143) between TB and SB. In 25% (36/143), SB detected additional tumor foci outside the target lesions. 70/143 patients subsequently underwent RP. The detection of tumor foci was congruent between mpMRI and prostatectomy specimen in 79% (55/70) of cases. Tumor foci were mpMRI occult in 21% (15/70) of cases. In the group with negative mpMRI (n = 111), biopsy was performed in 81 cases. Gleason ≥ 3+4 carcinoma was detected in 7% and Gleason 3+3 in 24% cases. CONCLUSION: There was a notable number of cases in which SB detected tumor foci that were mpMRI occult and could have been missed by TB alone. Therefore, additional systematic random biopsy is still required. A supplemental random biopsy should be considered depending on the overall clinical suspicion in negative mpMRI.

Progress in elementary school reading linked to growth of cortical responses to familiar letter combinations within visual word forms.

Learning to read depends on the ability to extract precise details of letter combinations, which convey critical information that distinguishes tens of thousands of visual word forms. To support fluent reading skill, one crucial neural developmental process is one's brain sensitivity to statistical constraints inherent in combining letters into visual word forms. To test this idea in early readers, we tracked the impact of two years of schooling on within-subject longitudinal changes in cortical responses to three different properties of words: coarse tuning for print, and fine tuning to either familiar letter combinations within visual word forms or whole word representations. We then examined how each related to growth in reading skill. Three stimulus contrasts-words versus pseudofonts, words versus pseudowords, pseudowords versus nonwords-were presented while high-density EEG Steady-State Visual Evoked Potentials (SSVEPs, n = 31) were recorded. Internalization of abstract visual word form structures over two years of reading experience resulted in a near doubling of SSVEP amplitude, with increasing left lateralization. Longitudinal changes (decreases) in brain responses to such word form structural information were linked to the growth in reading skills, especially in rapid automatic naming of letters. No such changes were observed for whole word representation processing and coarse tuning for print. Collectively, these findings indicate that sensitivity to visual word form structure develops rapidly through exposure to print and is linked to growth in reading skill. RESEARCH HIGHLIGHTS: Longitudinal changes in cognitive responses to coarse print tuning, visual word from structure, and whole word representation were examined in early readers. Visual word form structure processing demonstrated striking patterns of growth with nearly doubled in EEG amplitude and increased left lateralization. Longitudinal changes (decreases) in brain responses to visual word form structural information were linked to the growth in rapid automatic naming for letters. No longitudinal changes were observed for whole word representation processing and coarse tuning for print.

Drivers of Chronic Pathology Following Ischemic Stroke: A Descriptive Review.

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an ischemic event. One of the most clinically relevant aspects of the chronic sequelae of stroke is its extended negative effect on cognition. Cognitive impairment may be related to the deterioration and dysfunctional reorganization of white matter seen at later timepoints after stroke, as well as ongoing progressive neurodegeneration. The vasculature of the brain also undergoes significant insult and remodeling following stroke, undergoing changes which may further contribute to chronic stroke pathology. While inflammation and the immune response are well established drivers of acute stroke pathology, the chronicity and functional role of innate and adaptive immune responses in the post-ischemic brain and in the peripheral environment remain largely uncharacterized. In this review, we summarize the current literature on post-stroke injury progression, its chronic pathological features, and the putative secondary injury mechanisms underlying the development of cognitive impairment and dementia. We present findings from clinical and experimental studies and discuss the long-term effects of ischemic stroke on both brain anatomy and functional outcome. Identifying mechanisms that occur months to years after injury could lead to treatment strategies in the chronic phase of stroke to help mitigate stroke-associated cognitive decline in patients.

Comparative Analysis of Swine Antibody Responses following Vaccination with Live-Attenuated and Killed African Swine Fever Virus Vaccines.

African swine fever virus (ASFV) is circulating in many swine-producing countries, causing significant economic losses. It is observed that pigs experimentally vaccinated with a live-attenuated virus (LAV) but not a killed virus (KV) vaccine develop solid homologous protective immunity. The objective of this study was to comparatively analyze antibody profiles between pigs vaccinated with an LAV vaccine and those vaccinated with a KV vaccine to identify potential markers of vaccine-induced protection. Thirty ASFV seronegative pigs were divided into three groups: Group 1 received a single dose of an experimental LAV, Group 2 received two doses of an experimental KV vaccine, and Group 3 was kept as a non-vaccinated (NV) control. At 42 days post-vaccination, all pigs were challenged with the parental virulent ASFV strain and monitored for 21 days. All pigs vaccinated with the LAV vaccine survived the challenge. In contrast, eight pigs from the KV group and seven pigs from the NV group died within 14 days post-challenge. Serum samples collected on 41 days post-vaccination were analyzed for their reactivity against a panel of 29 viral structural proteins. The sera of pigs from the LAV group exhibited a strong antibody reactivity against various viral structural proteins, while the sera of pigs in the KV group only displayed weak antibody reactivity against the inner envelope (p32, p54, p12). There was a negative correlation between the intensity of antibody reactivity against five ASFV antigens, namely p12, p14, p15, p32, and pD205R, and the viral DNA titers in the blood of animals after the challenge infection. Thus, antibody reactivities against these five antigens warrant further evaluation as potential indicators of vaccine-induced protection.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

Functional Near-Infrared Spectroscopy of English-Speaking Adults With Attention-Deficit/Hyperactivity Disorder During a Verbal Fluency Task.

OBJECTIVE: Functional near-infrared spectroscopy (fNIRS) provides direct and quantitative assessment of cortical hemodynamic response. It has been used to identify neurophysiological alterations in medication-naïve adults with attention-deficit/hyperactivity disorder (ADHD). Hence, this study aimed to distinguish both medication-naïve and medicated adults with ADHD from healthy controls (HC). METHOD: 75 HCs, 75 medication-naïve, and 45 medicated patients took part in this study. fNIRS signals during a verbal fluency task (VFT) were acquired using a 52-channel system and relative oxy-hemoglobin changes in the prefrontal cortex were quantified. RESULTS: Prefrontal cortex hemodynamic response was lower in patients than HCs (p ≤ ≤.001). Medication-naïve and medicated patients did not differ in hemodynamic response or symptom severity (p > .05). fNIRS measurements were not associated with any clinical variables (p > .05). 75.8% patients and 76% HCs were correctly classified using hemodynamic response. CONCLUSION: fNIRS may be a potential diagnostic tool for adult ADHD. These findings need to be replicated in larger validation studies.

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Mutations in the Vicinity of the IRAK3 Guanylate Cyclase Center Impact Its Subcellular Localization and Ability to Modulate Inflammatory Signaling in Immortalized Cell Lines.

Interleukin-1 receptor-associated kinase 3 (IRAK3) modulates the magnitude of cellular responses to ligands perceived by interleukin-1 receptors (IL-1Rs) and Toll-like receptors (TLRs), leading to decreases in pro-inflammatory cytokines and suppressed inflammation. The molecular mechanism of IRAK3's action remains unknown. IRAK3 functions as a guanylate cyclase, and its cGMP product suppresses lipopolysaccharide (LPS)-induced nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activity. To understand the implications of this phenomenon, we expanded the structure-function analyses of IRAK3 through site-directed mutagenesis of amino acids known or predicted to impact different activities of IRAK3. We verified the capacity of the mutated IRAK3 variants to generate cGMP in vitro and revealed residues in and in the vicinity of its GC catalytic center that impact the LPS-induced NFκB activity in immortalized cell lines in the absence or presence of an exogenous membrane-permeable cGMP analog. Mutant IRAK3 variants with reduced cGMP generating capacity and differential regulation of NFκB activity influence subcellular localization of IRAK3 in HEK293T cells and fail to rescue IRAK3 function in IRAK3 knock-out THP-1 monocytes stimulated with LPS unless the cGMP analog is present. Together, our results shed new light on the mechanism by which IRAK3 and its enzymatic product control the downstream signaling, affecting inflammatory responses in immortalized cell lines.

High-Temperature Pasteurization Used at Donor Breast Milk Banks Reduces Melatonin Levels in Breast Milk.

Background and Objective: Donor human milk banks are used when breast milk directly from mothers is unavailable or insufficient. Breast milk contains melatonin, which exhibits a 24-hour pattern. Melatonin promotes sleep onset and is barely detected in daytime milk but rises in the evening and peaks early in the morning. Melatonin supports the development of an infant's own circadian rhythm and is important for neurodevelopment. Currently, donor banks pasteurize breast milk using a Holder Pasteurization (HoP) technique where breast milk is treated at a high temperature (+62°) for 30 minutes before cooling to eliminate any pathogens before it is given to infants. It is not known how the pasteurization process affects the melatonin levels in breast milk. The aim of this study was to investigate whether the pasteurization process reduces melatonin levels in breast milk. Materials and Methods: Ten night-time breast milk samples were collected and each divided into two groups; one group remained unpasteurized and the other group was pasteurized using the HoP technique. Results: Melatonin levels between the unpasteurized and pasteurized groups were compared. Results showed that there was a significant reduction after pasteurization (mean ± standard deviation = 51.92 pg/mL ± 19.54 versus 39.66 pg/mL ± 13.05, p = 0.01). Conclusions: It is important to understand that pasteurization can reduce melatonin levels in breast milk because this hormone is considered important to support the neurodevelopment of infants, especially those born preterm. Further focus on the effect of pasteurization techniques on melatonin in donor breast milk is warranted.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

Characteristics of oocytes that failed to fertilize after intracytoplasmic sperm injection.

Background: We assessed the morphologies of meiotic spindles in oocytes that failed to fertilize following intracytoplasmic sperm injection (ICSI) and identified factors contributing to failed fertilization. Methods: A total of 225 unfertilized oocytes were collected after ICSI. Oocytes were fixed and stained for tubulin and chromosomes. Meiotic spindle morphologies, chromosome alignment, and sperm nuclear decondensation were assessed to identify contributing factors to fertilization failure. We identified relationships between several factors and both abnormal spindle morphologies and sperm nuclear decondensation in oocytes that failed to fertilize. Results: Three causes for unfertilized oocytes after ICSI were identified: (I) the absence of a sperm nucleus in the ooplasm; (II) failed oocyte activation; and (III) defects in pronucleus formation or migration. The rate of disarranged polar spindles in oocytes collected from women older than 35 years (73.3%; 33/45 oocytes) was significantly higher than that of those collected from women 35 years and younger (50.4%; 68/135 oocytes; odds ratio [OR]: 2.71, 95% confidence interval [CI]: 1.29-5.69, p = 0.009). The proportion of unfertilized oocytes with abnormal spindles and chromosome misalignment was significantly higher in oocytes collected from women older than 35 years than those from women 35 years and younger (62.2% vs. 41.5%, p = 0.016). The proportion of partially decondensed chromatin in the abnormal sperm morphology group was significantly higher than in the normal sperm morphology group (66.7% versus 52.9%, OR: 1.78, 95% CI: 1.01-3.11, p = 0.044). Conclusions: The main contributor to the failure of oocytes to fertilize after ICSI is failed oocyte activation. The ICSI technique used, the maternal age, and sperm morphology are also contributing factors in fertilization failure after ICSI.

TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery From DNA Damage.

Transcriptional enhanced associate domain family members 1 to 4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors Yes-associated protein and transcriptional co-activator with PDZ-binding motif. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here, we employed an affinity purification mass spectrometry approach to identify nuclear interacting partners of TEADs. We performed affinity purification mass spectrometry experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to a nuclear localization sequence mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including X-ray repair cross-complementing protein 5 (XRCC5), X-ray repair cross-complementing protein 6 (XRCC6), poly(ADP-ribose) polymerase 1 (PARP1), and Rap1-interacting factor 1 (RIF1). In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by histone H2AX phosphorylated on S139 (γH2AX) and Rap1-interacting factor 1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.

Lexical and sublexical cortical tuning for print revealed by Steady-State Visual Evoked Potentials (SSVEPs) in early readers.

There are multiple levels of processing relevant to reading that vary in their visual, sublexical, and lexical orthographic processing demands. Segregating distinct cortical sources for each of these levels has been challenging in EEG studies of early readers. To address this challenge, we applied recent advances in analyzing high-density EEG using Steady-State Visual Evoked Potentials (SSVEPs) via data-driven Reliable Components Analysis (RCA) in a group of early readers spanning from kindergarten to second grade. Three controlled stimulus contrasts-familiar words versus unfamiliar pseudofonts, familiar words versus pseudowords, and pseudowords versus nonwords-were used to isolate coarse print tuning, lexical processing, and sublexical orthography-related processing, respectively. First, three overlapping yet distinct neural sources-left vOT, dorsal parietal, and primary visual cortex were revealed underlying coarse print tuning. Second, we segregated distinct cortical sources for the other two levels of processing: lexical fine tuning over occipito-temporal/parietal regions; sublexical orthographic fine tuning over left occipital regions. Finally, exploratory group analyses based on children's reading fluency suggested that coarse print tuning emerges early even in children with limited reading knowledge, while sublexical and higher-level lexical processing emerge only in children with sufficient reading knowledge. RESEARCH HIGHLIGHTS: Cognitive processes underlying coarse print tuning, sublexical, and lexical fine tuning were examined in beginning readers. Three overlapping yet distinct neural sources-left ventral occipito-temporal (vOT), left temporo-parietal, and primary visual cortex-were revealed underlying coarse print tuning. Responses to sublexical orthographic fine tuning were found over left occipital regions, while responses to higher-level linguistic fine tuning were found over occipito-temporal/parietal regions. Exploratory group analyses suggested that coarse print tuning emerges in children with limited reading knowledge, while sublexical and higher-level linguistic fine tuning effects emerge in children with sufficient reading knowledge.

Enhancing Annular Fissures and High-Intensity Zones: Pain, Internal Derangement, and Anesthetic Response at Provocation Lumbar Discography.

BACKGROUND AND PURPOSE: A high-intensity zone identified on preprocedural MR imaging is known to correlate with pain at provocation lumbar discography. The correlation between enhancing annular fissures and pain at provocation lumbar discography has not been comprehensively evaluated. The purpose of this study was to assess the pain response and imaging features at enhancing annular fissure nonoperated disc levels identified on preprocedural MR imaging with comparison with the high-intensity zone and nonenhancing disc levels in patients referred for provocation lumbar discography. MATERIALS AND METHODS: One-hundred nonoperated discs in 44 patients were retrospectively evaluated for an enhancing annular fissure on sagittal postcontrast T1-weighted pre-discogram MR imaging. Enhancing annular fissure discs were graded on the sagittal T2-weighted sequence (Grade 4: like CSF to Grade 1: negative/barely visible) for high-intensity-zone conspicuity. High-intensity-zone detection was performed independently. In the primary assessment, enhancing annular fissure and high-intensity zones were associated with pain response at provocation lumbar discography. Additional analysis included intradiscal anesthetic response and postdiscogram CT appearance. RESULTS: Thirty-nine discs demonstrated an enhancing annular fissure, with 23/39 demonstrating a high-intensity zone. The presence of a high-intensity zone predicted severe pain (concordant + nonconcordant; P = .005, sensitivity of 40%, specificity of 94%) and concordant pain (P = .007, sensitivity of 39%, specificity of 86%) at provocation lumbar discography. Enhancing annular fissures without a detected high-intensity zone were more frequently observed among severely painful (50%) and concordant (36%) discs than among discs negative for pain (9%; P = .01). This finding resulted in a substantially greater overall sensitivity of enhancing annular fissures for severe (P < .001, 64%) and concordant pain (P = .008, 61%), significantly improving the overall predictive ability of a high-intensity zone alone. A high-intensity zone went undetected in 9/11 Grade 1 disc levels with concordant pain present in 7/9. CONCLUSIONS: Consideration of enhancing annular fissures on preprocedural MR imaging substantially improves the prediction of severe/concordant pain in provocation lumbar discography.

Endoproteolysis of cellular prion protein by plasmin hinders propagation of prions.

Many questions surround the underlying mechanism for the differential metabolic processing observed for the prion protein (PrP) in healthy and prion-infected mammals. Foremost, the physiological α-cleavage of PrP interrupts a region critical for both toxicity and conversion of cellular PrP (PrP C ) into its misfolded pathogenic isoform (PrP Sc ) by generating a glycosylphosphatidylinositol (GPI)-anchored C1 fragment. During prion diseases, alternative ß-cleavage of PrP becomes prominent, producing a GPI-anchored C2 fragment with this particular region intact. It remains unexplored whether physical up-regulation of α-cleavage can inhibit disease progression. Furthermore, several pieces of evidence indicate that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 play a much smaller role in the α-cleavage of PrP C than originally believed, thus presenting the need to identify the primary protease(s) responsible. For this purpose, we characterized the ability of plasmin to perform PrP α-cleavage. Then, we conducted functional assays using protein misfolding cyclic amplification (PMCA) and prion-infected cell lines to clarify the role of plasmin-mediated α-cleavage during prion propagation. Here, we demonstrated an inhibitory role of plasmin for PrP Sc formation through PrP α-cleavage that increased C1 fragments resulting in reduced prion conversion compared with non-treated PMCA and cell cultures. The reduction of prion infectious titer in the bioassay of plasmin-treated PMCA material also supported the inhibitory role of plasmin on PrP Sc replication. Our results suggest that plasmin-mediated endoproteolytic cleavage of PrP may be an important event to prevent prion propagation.