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Abstract KRAS belongs to a family of small GTPases that act as binary switches upstream of several signalling cascades, controlling proliferation and survival of cells. Mutations in KRAS drive oncogenesis, especially in pancreatic, lung, and colorectal cancers (CRC). Although historic attempts at targeting mutant KRAS with small molecule inhibitors have proven challenging, there are recent successes with the G12C, and G12D mutations. However, clinically important RAS mutations such as G12V, G13D, Q61L, and A146T, remain elusive drug targets, and insights to their structural landscape is of critical importance to develop novel, and effective therapeutic concepts. We present a fully open, P-loop exposing conformer of KRAS G13D by X-ray crystallography at 1.4–2.4 Å resolution in Mg2+-free phosphate and malonate buffers. The G13D conformer has the switch-I region displaced in an upright position leaving the catalytic core fully exposed. To prove that this state is druggable, we developed a P-loop-targeting monoclonal antibody (mAb). The mAb displayed high-affinity binding to G13D and was shown using high resolution fluorescence microscopy to be spontaneously taken up by G13D-mutated HCT 116 cells (human CRC derived) by macropinocytosis. The mAb inhibited KRAS signalling in phosphoproteomic and genomic studies. Taken together, the data propose novel druggable space of G13D that is reachable in the cellular context. It is our hope that these findings will stimulate attempts to drug this fully open state G13D conformer using mAbs or other modalities.

Abstract The mitoribosome translates mitochondrial mRNAs and regulates energy conversion that is a signature of aerobic life forms. We present a 2.2 Å resolution structure of human mitoribosome together with validated mitoribosomal RNA (rRNA) modifications, including aminoacylated CP-tRNAVal. The structure shows how mitoribosomal proteins stabilise binding of mRNA and tRNA helping to align it in the decoding center, whereas the GDP-bound mS29 stabilizes intersubunit communication. Comparison between different states, with respect to tRNA position, allowed us to characterize a non-canonical L1 stalk, and molecular dynamics simulations revealed how it facilitates tRNA transitions in a way that does not require interactions with rRNA. We also report functionally important polyamines that are depleted when cells are subjected to an antibiotic treatment. The structural, biochemical, and computational data illuminate the principal functional components of the translation mechanism in mitochondria and provide a description of the structure and function of the human mitoribosome.

Purpose – This research aims to determine the effect of using Canva media as a means of delivering material on students' ability to write negotiation texts. This is motivated by students' low writing skills, especially in negotiation text material. Method – This research uses a quantitative experimental method, namely the method used to find out how the independent variable, or in this research the use of Canva media influences the dependent variable, namely the student's ability to write negotiation texts. The population in this study was all class The data collection technique used is an assignment test to determine students' ability to write negotiation texts. Findings – The results of this research obtained an average of 78.78 for the experimental class and 66.12 for the control class. The results of the data requirements test show that the data for both classes are normally distributed and homogeneous. In the t-test, tcount > ttable = 6.3618 > 1.6698. Thus, it can be concluded that there was a significant effect of using Canva media on the ability to write student negotiation texts. Research Implications – This research proves that learning media is one of the important aspects of the success of teaching and learning activities. Interesting learning media will make it easier for teachers to convey material and students can also more easily understand and master learning. The Canva Application media which can stimulate images, and videos can make it easier for students to understand the material in searching for information and topics in written material, besides this, students play a more active role in learning activities to write negotiation texts.

Abstract We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6–2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.

Rendahnya penguasaan konsep yang dimiliki peserta didik menyebabkan hasil belajar seringkali jauh dari standar penilaian terutama pada mata pelajaran IPA. Penelitian ini secara umum bertujuan untuk mengembangkan media pembelajaran komik digital yang dapat menanamkan penguasaan konsep peserta didik. Penelitian ini menggunakan pendekatan kuantitatif dengan metode kuantitatif-deskriptif. Metode yang digunakan adalah Research & Development (R&D) yang merupakan metode ilmiah untuk memperoleh data sehingga dapat dipergunakan untuk menghasilkan, mengembangkan, dan memvalidasi produk. Media pembelajaran komik digital dikembangkan melalui tahapan validasi produk terlebih dahulu yang melibatkan ahli materi dan media untuk mengetahui kelayakan dan keefektifan produk. Kemudian, produk komik digital diujicobakan untuk mengetahui penguasaan konsep peserta didik setelah mengikuti kegiatan pembelajaran. Partisipan dalam penelitian ini adalah 23 orang peserta didik kelas V di salah satu SD Negeri yang berada di Kabupaten Karimun, Provinsi Kepulauan Riau. Hasil penelitian menunjukkan bahwa komik digital layak dan efektif untuk digunakan sebagai media pembelajaran yang dapat membantu guru dalam kegiatan pembelajaran IPA. Media pembelajaran komik digital juga dapat meningkatkan penguasaan konsep peserta didik kelas V yang dibuktikan dengan adanya peningkatan hasil belajar yang diperoleh peserta didik.

Emerging SARS-CoV-2 variants of concern (VOCs) raises concerns regarding vaccine efficacy. Here, the authors evaluate the neutralizing antibody, and cellular response elicited following inactivated vaccine immunization, and mRNA booster, against the Omicron variant.

ABSTRAK Penelitian ini bertujuan untuk mengetahui pengaruh menggunakan model pembelajaran Take and give terhadap hasil belajar pada Subtema 1 Cara Tubuh Mengolah Udara Bersih. Penelitian ini menggunakan metode pendekatan Kuantitatif. untuk menguji instrumen penelitian dengan menggunakan Uji Validitas, Reliabilitas,Uji tingkat kesukaran, Daya pembeda tes. pengumpulan data dengan tahap observasi, Tes awal dan pemberian serta tes akhir Teknik analisis data menggunakan Mean, Varians, dan uji Homogenitas, serta pengujian Hipotesis dengan uji t . Hasil penelitian menunjukkan: (1) Uji homogenitas data dengan nilai signifikasi > 0,05 maka dikatakan homogen apabila nilai sig based of mean > 0,05 hasil penelitian menunjukkan nilai based of mean 114 > 0,05 sehingga dapat disimpulkan bahwa varian data post test-kelas eksperimen dan post-test kontrol sama atau homogen. Berdasarkan hasil tersebut dapat. (2) Output pair 2 diperoleh nilai sig (2 tailed) sebesar 0,000 maka 0,000 > 0,05. Berdasarkan hasil tersebut dapat disimpulkan H0 ditolak dan Ha diterima. Berdasarkan penelitian disimpulkan: terdapat hubungan positif dan signifikan pengaruh model take and give terhadap hasil belajar siswa. Hasil tersebut dibuktikan hasil uji hipotesis dengan rumus uji t, dimana t hitung yang diperoleh nilai sig (2 tailed) sebesar 0,00 > 0,05 sehingga dapat ditarik kesimpulan Ho ditolak dan Ha diterima. Kata Kunci: Model Take and give, Subtema 1 Cara Tubuh Mengolah Udara Bersih, dan Hasil Belajar ABSTRACT This study aims to determine the effect of using the Take and give learning model on learning outcomes in Subtheme 1 How the Body Processes Clean Air. This study uses a quantitative approach. to test the research instrument using Validity Test, Reliability, Difficulty level test, Distinguishing test. data collection with the observation stage, pre-test and administration and post-test. Data analysis techniques used the Mean, Variance, and Homogeneity test, as well as hypothesis testing with the t-test. The results showed: (1) The homogeneity test of the data with a significance value > 0.05 then it was said to be homogeneous if the sig-based mean value > 0.05. -the experimental class and the control post-test are the same or homogeneous. Based on these results can. (2) Output pair 2 obtained sig (2 tailed) value of 0.000, then 0.000 > 0.05. Based on these results, it can be concluded that H0 is rejected and Ha is accepted. Based on the research concluded: there is a positive and significant relationship the effect of the take and give model on student learning outcomes. These results are evidenced by the results of hypothesis testing with the t test formula, where t count obtained sig (2 tailed) value of 0.00 > 0.05 so that it can be concluded that Ho is rejected and Ha is accepted. Keywords: Take and give Model, Sub-theme 1 How the Body Processes Clean Air, and Learning Outcomes

Here, Roxhed et al. develop a multiplexed approach to screen IgG and IgM levels against several SARS-CoV-2 proteins in home-sampled dried blood spots and estimate seroprevalence of 12.5% in Stockholm in spring of 2020.

Work fatigue is a form of body protection mechanism to avoid further damage and recovery after rest. Tire patch workers who work on the roadside are very vulnerable to work fatigue. This study aims to determine the relationship between fluid consumption, workload and heat stress with work fatigue. This type of research is observational with cross sectional approach. The sample of this research is 44 tire patch workers on the edge of Jalan Mugas Raya Semarang. Data analysis was performed with the Pearson Chi Square test. The results showed that workers who experienced high category of work fatigue by 50% and obtained a relationship between fluid consumption (p = 0.043), workload (p = 0.004), heat pressure (p = 0.033) with work fatigue. The conclusion is that the majority of workers who use tire patches on the roadside experience work fatigue, so they need to get health guidance.

Summary: Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15–28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.

Introduction Calcium hydroxide (Ca(OH) 2) is the material of choice for pulp therapy. However, Ca(OH) 2 has drawbacks such as toxicity, poor sealing, and tunnel defect formation. Alternative materials have been developed to provide more biocompatible materials with better dentin formation ability. The objective of this study was to evaluate the effect of composites containing gelatin (G), chitosan (CH), tetraethyl orthosilicate (TEOS), and Ca(OH) 2, namely G-CH-TEOS-Ca(OH) 2 (Extended data) on inflammation of the dental pulp (expression of COX-2, PGP 9.5, TNF-α, and neutrophil number). Materials and methods A total of 16 Wistar rat models of acute pulp injury were prepared and divided into two groups, treatment and control, 8 with each. In the treatment group, we applied a pulp-capping material using G-CH-TEOS-Ca(OH) 2 and Ca(OH) 2. On the 1 st and 3 rd days, rats were sacrificed. Tissue samples from 4 rats in each group were processed for histological preparation. COX-2, PGP 9.5, and TNF-α were observed using immunohistochemical (IHC) staining, and neutrophil numbers were observed using hematoxylin-eosin staining. Image analysis of COX-2, PGP 9.5, and TNF-α expression was performed using ImageJ software. Results The results showed a decrease in COX-2 expression, but not significantly while PGP 9.5 and TNF-α expression were significantly higher than those in the control group. Neutrophil numbers were lower in the treatment group than in the control group, but the difference was not statistically significant. Conclusion The G-CH-TEOS-Ca(OH) 2 composite material may have potential as an exposed pulp medicament by reducing inflammation (COX-2 expression and number of neutrophils) and increasing the regeneration factor (TNF-α expression) and nerve (PGP 9.5 expression).

Introduction In recent years, the number of cardiac surgeries has been on the rise. Several predictive models have been developed to assess the risk of mortality for these patients. EuroSCORE II, a widely used model, demonstrates good discrimination and calibration for the European population, but its accuracy may vary in the Indonesian population. The purpose of this study was to develop a scoring model tailored to Indonesian population, which may have better accuracy in assessing in-hospital mortality risk among adult cardiac surgery patients. Method A retrospective study was conducted using medical records of adult cardiac surgery patients from four participating hospitals. Potential risk factors were included as variables and analyzed using bivariate and multivariable logistic regression with the L-backward method. Bootstrapping was applied to enhance the model’s validity. Receiver operating characteristic (ROC) curves were created for each model, and the area under the curve (AUC) was calculated to assess discrimination ability, while the Hosmer-Lemeshow test was used to evaluate calibration. Results We extracted data from 4,875 patients, with a mean age of 50.41 years, and most patients were men (63.1%). The majority of patients were in NYHA class I-II. The in-hospital mortality rate was 6.5%. From 62 potential variables, 13 variables were included in the final model. Our new model demonstrated strong discrimination and calibration (AUC 0.7564; Hosmer-Lemeshow p = 0.9510). Conclusion The newly developed scoring model exhibited good discrimination and calibration, making it a promising tool for predicting in-hospital mortality in adult cardiac surgery patients in Indonesia.

* Background Goal-directed perfusion (GDP) aims to balance oxygen delivery (DO 2) and consumption (VO 2) in cardiac surgery. Elevated lactate during CPB is common and linked to higher morbidity and mortality. Evaluating lactate with base excess (BE) is vital due to their relationship. Reducing severe BE and lactate predicts cardiac surgery outcomes better. Methods Fifty adult patients undergoing cardiac surgery with CPB were randomly assigned to either the GDP group or the conventional group. In the GDP group, the priming solution was adjusted to target a hematocrit (HCT) level of 24 to 27% with a pump flow of 1.8 to 2.2 L/min/m2 to maintain mean arterial pressure (MAP) between 60 and 65 mmHg. The primary outcomes was oxygen delivery index (DO 2i). Results There were increasing trends in lactate levels and decreasing trends in BE levels at all timeframes. The GDP mean difference of lactate [1.504 (1.52); p < 0.001] and BE [-0.87 (2.93); p = 0.22] levels showed better value in the GDP group, with statistically significant increased values in the control group for BE [-1.667 (2.93); p = 0.017] and lactate levels [2.215 (2.919); p < 0.001]. The postoperative outcome showed a significant difference in AKI and ventilator time. Conclusions The GDP low flow CPB compared with conventional flow CPB maintained DO 2 matched with VO 2 with a better clinical values in the lactate and BE levels and significantly lowered AKI and ventilator duration in cardiac surgery.

Background The interaction between Streptococcus mutans (S. mutans) and Veillonella species ( Veillonella spp.) is unclear. This study aims to investigate the interaction between S. mutans and Veillonella spp. on caries development using systematic review. Methods This systematic review was accorded to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Three electronic databases, namely PubMed, Embase, and the Cochrane library, were used to conduct a systematic search for eligible studies from their inception until July 18, 2023. PROSPERO registration number was No. CRD42023445968. Results We initially identified 4,774 articles. After eliminating duplicates and irrelevant articles, 11 studies met the inclusion criteria. The studies revealed important aspects of the relationship between S. mutans and Veillonellae spp. in dental caries. One significant finding is that Veillonellae spp. can affect the acid production capacity of S. mutans. Some studies indicate that Veillonellae spp. can inhibit the acid production by S. mutans, potentially reducing the cariogenic process. Another aspect is the competition for substrates. Veillonellae spp. utilize lactic acid, which is a by product of S. mutans metabolism, as a source of carbon. This metabolic interaction may decrease the availability of lactic acid for S. mutans, potentially influencing its cariogenic potential. Conclusions This systematic review highlights the emerging evidence on the interaction between S. mutans and Veillonellae spp. in dental caries. The findings suggest that Veillonellae spp. can modulate the acid production, and substrate competition of S. mutans, potentially influencing the cariogenic process.