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Examining prestructured β-actin peptides as substrates of histidine methyltransferase SETD3

The Nτ-His73 methylation of β-actin by histidine methyltransferase SETD3 is required for the integrity of the cellular cytoskeleton. Modulation of SETD3 activity in human cells facilitates cancer-like changes to the cell phenotype. SETD3 binds β-actin in an extended conformation, with a conserved bend-like motif surrounding His73. Here, we report on the catalytic specificity of SETD3 towards i, i + 3 stapled β-actin peptides possessing a limited conformational freedom surrounding the His73 substrate residue via positions Glu72 and Ile75. Stapled β-actin peptides were observed to be methylated less efficiently than the linear β-actin peptide. None of the stapled β-actin peptides efficiently inhibited the SETD3-catalyzed Nτ-His73 methylation reaction. Molecular dynamics simulations demonstrated that the unbound and SETD3-bound β-actin peptides display different backbone flexibility and bend-like conformations, highlighting their important role in substrate binding and catalysis. Overall, these findings suggest that reduced backbone flexibility of β-actin prevents the formation of optimal protein-peptide interactions between the enzyme and substrate, highlighting that the backbone flexibility needs to be considered when designing β-actin-based probes and inhibitors of biomedically important SETD3.

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Effect of CD4 count on Mycobacterium tuberculosis infection rates in people living with HIV: a comparative study in prison and community

To evaluate the impact of the CD4 count on ESAT6-CFP10 (EC) skin test, QuantiFERON-TB Gold In-tube test (QFT) and tuberculin skin test (TST) in a large prison and communities in Jiangsu Province among people living with HIV (PLHIV). Participants in communities were tested with the QFT and EC skin test and in prison were tested with the QFT, TST and EC skin test. A 4-knotted restricted cubic spline fitted for Logistic models was used to explore the cutoff point of CD4 count and the associations between changes in CD4 count and Mycobacterium tuberculosis (M.tb) infection. Among 1,815 PLHIV included, 19.3% (350) were from prisons and 80.7% (1465) were identified through community screenings. M.tb infection rates were 12.2% and 8.3% through QFT and EC tests, respectively. Odd Ratios (ORs) for infection increased with CD4 counts, peaking at 618 cells/mm3 for EC, 392 cells/mm3 for QFT, then plateaued. However, the pattern differed for EC between prison and screening scenarios. In prison settings, M.tb infection increased with CD4 count from 0 to 350 cells/mm3, plateaued until 500 cells/mm3, and then persistently increased. Conversely, for community, ORs decreased until 300 cells/mm3, followed by an increase between 300 and 729 cells/mm3, after which they continued to rise persistently. Our cross-sectional study among PLHIV revealed a higher rate of M.tb infection in prison compared to the community. The relationship between CD4 count and infection became negative after a certain threshold. This pivotal point differed with detection methods, with QFT showing lower CD4 thresholds than EC.

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Narrative predicts cardiac synchrony in audiences

Audio-visual media possesses a remarkable ability to synchronise audiences’ neural, behavioural, and physiological responses. This synchronisation is considered to reflect some dimension of collective attention or engagement with the stimulus. But what is it about these stimuli that drives such strong engagement? There are several properties of media stimuli which may lead to synchronous audience response: from low-level audio-visual features, to the story itself. Here, we present a study which separates low-level features from narrative by presenting participants with the same content but in separate modalities. In this way, the presentations shared no low-level features, but participants experienced the same narrative. We show that synchrony in participants’ heart rate can be driven by the narrative information alone. We computed both visual and auditory perceptual saliency for the content and found that narrative was approximately 10 times as predictive of heart rate as low-level saliency, but that low-level audio-visual saliency has a small additive effect towards heart rate. Further, heart rate synchrony was related to a separate cohorts’ continuous ratings of immersion, and that synchrony is likely to be higher at moments of increased narrative importance. Our findings demonstrate that high-level narrative dominates in the alignment of physiology across viewers.

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Humeral retroversion, shoulder range of motion, and functional mobility in striking martial arts athletes

The aim of the study was to evaluate humeral retroversion, shoulder range of motion, and functional mobility in karatekas, boxers, kickboxers, and mixed martial arts fighters. This study investigated adaptive alterations in striking martial arts. Forty young healthy participants took part in the study. 20 people who professionally trained in boxing, kickboxing, karate, and Mixed Martial Arts (MMA) fighters (age: 23.5 ± 7.1, age of participation 11.8 ± 3.65, sports experience 9.55 ± 5.13, body weight 79.2 ± 13 kg, BMI 24.4 ± 3.3) were qualified for the group of athletes. 20 people (age: 27 ± 5.5, body weight 79.4 ± 7.4, BMI 24.5 ± 1.2) were included in the control group, who had no previous experience with striking combat sports. An ultrasound device and a digital inclinometer were used for the examination of the humeral retroversion angle. The mobility of the shoulder was also tested using the Functional Movement Screen (FMS). There was a significant (p < 0.001, r = 0.92) asymmetry between the dominant and non-dominant limb in the humeral retroversion angle in the athlete group. A statistically significant moderate correlation (p < 0.05) was found between the value of the retroversion angle and the range of motion of passive and active internal rotation, and external rotation, and the shoulder mobility in the FMS test. However, there were no statistically significant differences (p > 0.05) in the humeral retroversion angles between groups. The striking martial arts athletes do not exhibit significant differences in humeral retroversion compared to non-athletes, however they display notable asymmetry between limbs, with higher values in the non-dominant arm. Additionally, the observed correlation between humeral retroversion and shoulder rotation range of motion highlights the potential impact of humeral retroversion on upper limb performance and injury risk.

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Development of an ultrasound-based clinical decision rule to rule-out diverticulitis

The concern for diverticulitis often leads to the use of computed tomography (CT) scans for diagnosis. We aim to develop an ultrasound-based clinical decision rule (CDR) to confidently rule-out the disease without requiring a CT scan. We analyzed data from a prospective study of adult emergency department (ED) patients with suspected diverticulitis who underwent both bedside ultrasound (US) and CT. Patient history, physical examination, laboratory findings, and US results were used to create a CDR via a recursive partitioning model designed to prioritize sensitivity, with a loss matrix heavily penalizing false negatives. We calculated the test characteristics for this CDR (TICS-Rule) and assessed the potential reduction in CT scans and ED length of stay. Data from 149 patients (84 female; mean age 58 ± 16) were used to develop the TICS-Rule. The final model integrates US diagnosis of simple and complicated diverticulitis, along with variables of heart rate, age, history of diverticulosis, vomiting, and leukocytosis. Negative US results and a heart rate below 100 effectively excluded diverticulitis. The sensitivity increased from 54.5% (32.2–75.6) in the US alone to 100% (84.6–100%) for complicated diverticulitis in the model. The TICS-Rule missed no cases of complicated diverticulitis but one case of simple diverticulitis. The median time from ED greeting to US interpretation was 103 min (IQR 62–169), compared to 285 min (IQR 229–372) for CT. The TICS-Rule uses a combination of negative US and heart rate less thanQ1 100 to exclude diverticulitis without the need for a CT scan. Integration of the TICS-Rule offers a promising enhancement to clinical decision-making while reducing both CT use and ED length of stay.

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Experimental evidence of phase transition of silica polymorphs in basaltic eucrites: implications for thermal history of protoplanetary crust

Silica polymorphs occur under various pressures and temperature conditions, and their characteristics can be used to better understand the complex metamorphic history of planetary materials. Here, we conducted isothermal heating experiments of silica polymorphs in basaltic eucrites to assess their formation and stability. We revealed that each silica polymorph exhibits different metamorphic responses: (1) Quartz recrystallizes into cristobalite when heated at ≥ 1040 °C. (2) Monoclinic (MC) tridymite recrystallizes into no other polymorphs when heated at ≤ 1070 °C. (3) Silica glass recrystallizes into quartz when heated at 900–1010 °C, and recrystallize into cristobalite when heated at ≥ 1040 °C. These results suggest that MC tridymite in eucrites does not recrystallize into other polymorphs during the reheating events, nor does it recrystallize from other silica phases below the solidus temperature of eucrite (~ 1060 °C). Additionally, we found that pseudo-orthorhombic (PO) tridymite crystallizes from quenched melts in the samples heated at ≥ 1070 °C. Previously, cristobalite has been considered as the initial silica phase, which crystallizes from eucritic magma. Our findings suggest that the first crystallizing silica minerals may not always be cristobalite. These require a reconsideration of the formation process of silica minerals in eucrites.

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The role of adjuvant endocrine treatment in ER+, PR−, HER2− early breast cancer: a retrospective study of real-world data

Purpose: Estrogen receptor-positive (ER+), progesterone receptor-negative (PR-) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) often developed resistance to endocrine treatment (ET). We aimed to explore (1) the different clinicopathological features between ER+/PR+/HER2- and ER+/PR-/HER2- BC, and (2) whether ER+/PR-/HER2- early BC patients could benefit from adjuvant ET. Methods: All patients treated for ER+/HER2- early BC who underwent surgery between 2010 and 2021 from a BC database in China were retrospectively examined. The cases followed up for less than six months were excluded. Results: The records of ER+/PR+/HER2- (n = 10843) and ER+/PR-/HER2- BC (n = 1193) cases were reviewed, with median follow-up times of 35.8 and 47.0 months, respectively. Compared with ER+/PR+/HER2- cases, ER+/PR-/HER2- BC occurred more in postmenopausal women (73.1% vs. 52.9%, p = 0.000) and were more likely to be T > 2 cm (40.6% vs. 37.6%, p = 0.048) and Ki67 > 20%+ (48.1% vs. 36.9%, p = 0.000). However, ER+/PR-/HER2- cases had fewer nodal involvement (32.9% vs. 36.9%, p = 0.000). Approximately 82.2% (981/1193) of ER+/PR-/HER2- patients received ET, while approximately 17.8% (212/1193) did not. Compared to patients did not receive adjuvant ET, the ET group had similar disease-free survival (DFS) (HR = 1.33, 95% confidence interval (CI): 0.68–2.59, p = 0.444) and overall survival (OS) (HR = 1.17, 95%CI: 0.37–3.68, p = 0.799). 65.7% of recurrent ER+/PR-/HER2- patients experienced distant relapse (65.7% vs. 48.2% (for ER+/PR + cases), p = 0.011). By comparison, recurrent ER+/PR+/HER2- patients were more likely to experience only local relapse (31.6% vs. 14.9% (for ER+/PR- cases), p = 0.007). Conclusions: ER+/PR-/HER2- BC was a special subtype with aggressive clinicopathological features and more tend to have distant metastasis rather than nodal involvement or local relapse. ER+/PR-/HER2- early BC did not seem to benefit from adjuvant ET.

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Association between KRAS mutation and alcohol consumption in Brazilian patients with colorectal cancer

Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide. Detection before metastasis and efficient treatment of disease significantly improve patient survival and quality of life. However, limitations in diagnosis and postoperative surveillance are associated with low CRC detection and survival rates. Thus, this project aimed to evaluate the molecular profile of patients diagnosed with CRC, as molecular biomarkers constitute a new frontier for diagnosis, treatment and prognosis. Methods and Results: 42 patients were included in the study, predominantly male (59.5%), with a median age of 63 years (SD: 10.0; min: 41; max: 83). The majority of primary tumors were located in the rectum (38.1%), in the sigmoid (33.3%) and in the ascending (21.4%) colon. We evaluated the genes KRAS, NRAS, BRAF, EGFR and TP53 using Sanger sequencing. Somatic and germline mutations were found in the KRAS, EGFR and TP53 genes, with the most common somatic alteration being rs121913529 in KRAS. This variant was also strongly associated with alcoholism (p = 0.002). Furthermore, patients with somatic mutations in TP53 had significantly higher mortality compared to those with wild-type alleles (OR: 11.2; 95% CI 1.25–2.45). Conclusions: Our findings support a relationship between alcohol consumption and the rs121913529 mutation, which is classified as pathogenic for colorectal cancer. Thus, further studies investigating the link between alcohol consumption, colorectal carcinogenesis and tumor progression ought to be conducted.

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