Search

Abstract Introduction The treatment options for moderate to severe psoriasis (msPsO) in China have been greatly increased with the approvals of biologics. However, the unmet needs and treatment preferences of systemic treatments for msPsO in China remain unclarified. Methods Fifty dermatologists and 300 patients with msPsO (41% with severe psoriasis) were surveyed for effectiveness, safety, treatment convenience, and treatment preferences (using a choice-based conjoint questionnaire). Descriptive statistics and conjoint simulation analyses were employed to summarize survey information and assess treatment preferences. Results Both patients and dermatologists reported shorter treatment duration for oral drugs (2.7–6.2 months) than that for biologics (9.5–17.0 months). The most frequently reported treatment discontinuation reasons by the surveyed patients and dermatologists were unsatisfactory effectiveness (average 84.5%) for oral drugs and loss of efficacy over time (average 68.5%) for biologics. Commonly reported treatment inconveniences included regular lab tests for traditional oral drugs (average 71.5%) and administration assistance for biologics (average 58.0%). Injection site reactions (average 51.5%) and needle fear (average 35.5%) were frequently reported for biologics among the surveyed patients and dermatologists. Once-daily oral treatment was preferred over biweekly subcutaneous injection treatment when the two had comparable attributes (average in patients 87.1% vs. 12.9%; average in dermatologists 93.4% vs. 6.6%). Conclusions Unmet needs of systemic treatments remain for msPsO in China. Once-daily oral treatment is preferred over biweekly subcutaneous injections to treat msPsO when other treatment attributes are comparable.

Abstract Pancreatic cancer (PC) is mainly derived from the exocrine pancreatic ductal epithelial cells, and it is strongly aggressive malignant tumor. Due to its insidious onset and the lack of effective diagnostic biomarkers, PC currently remains one of the main causes of cancer-related mortality worldwide. Recent studies have found that hsa_circ_0001846 is involved in the progression of multiple cancers and has the potential to become biomarkers, but its function and mechanism in PC remains unclear. We found by qRT-PCR experiments that hsa_circ_0001846 was upregulated in PC cells and tissues, while circBase, Sanger sequencing, agarose gel electrophoresis and FISH experiments identified the splicing site, ring structure and cellular localization of hsa_circ_0001846. Various functional experiments by using the construction of small interfering RNA targeting hsa_circ_0001846 and overexpression plasmid demonstrated that hsa_circ_0001846 promoted the proliferation, migration and invasion of PC cells. Moreover, the tumor weight and volume of nude mice were significantly reduced after the stable knockdown of hsa_circ_0001846. In the mechanism exploration, RNA pull-down experiments and dual-luciferase experiments helped us to determine that hsa_circ_0001846 regulated the KRAS expression by sponging miR-204-3p in PC, thus playing a pro-cancer role. In this study, the effect of miR-204-3p on PC was also explored for the first time, and we found that knockdown of miR-204-3p reversed the tumor suppressive effect caused by silencing hsa_circ_0001846, and silencing KRAS also rescued the pro-cancer effect caused by overexpression of hsa_circ_0001846. In conclusion, our study revealed the pro-cancer role of hsa_circ_0001846 in PC, and for the first time identified the mechanism that hsa_circ_0001846 regulated KRAS by sponging miR-204-3p to promote PC progression and had the potential to become a cancer biomarker.

Background: Cardiac remodeling is a common pathological feature in many cardiac diseases, characterized by cardiac hypertrophy and fibrosis. Triptolide (TP) is a natural compound derived from Tripterygium wilfordii Hook F. However, the related mechanism of it in cardiac remodeling has not been fully understood. Methods and results: Transverse aortic constriction (TAC)-induced cardiac hypertrophic mouse model and angiotensin II (Ang II)-induced cardiomyocytes hypertrophic model were performed. Firstly, the results indicate that TP can improve cardiac function, decreased cardiomyocyte surface area and fibrosis area, as well as lowered the protein expressions of brain natriuretic peptide (BNP), β-major histocompatibility complex (β-MHC), type I and III collagen (Col I and III). Secondly, TP suppressed cardiac pyroptosis, and decreased the levels of Interleukin-1β (IL-1β), Interleukin-18 (IL-18) by Enzyme-linked immunosorbent assay (ELISA), and pyroptosis-associated proteins. Furthermore, TP enhanced the expressions of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). Interestingly, when Nrf2 was silenced by siRNA, TP lost its properties of reducing pyroptosis and cardiac hypertrophy. In addition, in the Transforming Growth Factor β1 (TGF-β1)-induced primary human coronary artery endothelial cells (HCAEC) model, TP was found to inhibit the process of endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial-specific markers and the gain of mesenchymal markers. This was accompanied by a suppression of Slug, Snail, and Twist expression. Meanwhile, the inhibitory effect of TP on EndMT was weakened when Nrf2 was silenced by siRNA. Lastly, potential targets of TP were identified through network pharmacology analysis, and found that Ubiquitin-Specific Protease 14 (USP14) was one of them. Simultaneously, the data indicated that decrease the upregulation of USP14 and Kelch-like ECH-Associated Protein 1 (Keap1) caused by cardiac remodeling. However, Keap1 was decreased and Nrf2 was increased when USP14 was silenced. Furthermore, CoIP analysis showed that USP14 directly interacts with Keap1. Conclusion: TP can observably reduce pyroptosis and EndMT by targeting the USP14/Keap1/Nrf2 pathway, thereby significantly attenuating cardiac remodeling.

Abstract Circular RNAs (circRNAs) play critical regulatory roles in cancer biological processes. Nevertheless, the contributions and underlying mechanisms of circRNAs to pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. Dysregulated circRNAs between cancerous tissues and matched adjacent normal tissues were identified by circRNA microarray in PDAC. The biological effect of hsa_circ_007367 both in vitro and in vivo was demonstrated by gain- and loss-of-function experiments. Further, dual-luciferase reporter and RNA pull-down assays were performed to confirm the interaction among hsa_circ_007367, miR-6820-3p, and Yes-associated protein 1 (YAP1). The expression of hsa_circ_007367 and YAP1 were detected by in situ hybridization (ISH) and immunohistochemistry (IHC) using tissue microarray (TMA) in 128 PDAC samples. We first identified that a novel circRNA, hsa_circ_0007367, was markedly upregulated in PDAC tissues and cells. Functionally, in vivo and in vitro data indicated that hsa_circ_0007367 promotes the proliferation and metastasis of PDAC. Mechanistically, we confirmed that hsa_circ_0007367 could facilitate the expression of YAP1, a well-known oncogene, by sponging miR-6820-3p, which function as a tumor suppresser in PDAC cells. The results of ISH and IHC demonstrated that hsa_circ_0007367 and YAP1 were upregulated in PDAC tissues. Furthermore, clinical data showed that higher hsa_circ_0007367 expression was correlated with advanced histological grade and lymph node metastasis in PDAC patients. In conclusion, our findings reveal that hsa_circ_0007367 acts as an oncogene via modulating miR-6820-3p/YAP1 axis to promote the progression of PDAC, and suggest that hsa_circ_0007367 may serve as a potential therapeutic target for treatment of PDAC.

Cardiac microvascular dysfunction is associated with cardiac hypertrophy and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac hypertrophy. However, the potential roles and underlying mechanisms of lncRNAs in cardiac microvascular dysfunction have not been explicitly delineated. Our results confirmed that cardiac microvascular dysfunction was related to cardiac hypertrophy and ferroptosis of cardiac microvascular endothelial cells (CMECs) occurred during cardiac hypertrophy. Using a combination of in vivo and in vitro studies, we identified a lncRNA AABR07017145.1, named as lncRNA AAB for short, and revealed that lncRNA AAB was upregulated in the hearts of cardiac hypertrophy rats as well as in the Ang II-induced CMECs. Importantly, we found that lncRNA AAB sponged and sequestered miR-30b-5p to induce the imbalance of MMP9/TIMP1, which enhanced the activation of transferrin receptor 1 (TFR-1) and then eventually led to the ferroptosis of CMECs. Moreover, we have developed a delivery system based on neutrophil membrane (NM)-camouflaged mesoporous silica nanocomplex (MSN) for inhibition of cardiac hypertrophy, indicating the potential role of silenced lncRNA AAB (si-AAB) and overexpressed miR-30b-5p as the novel therapy for cardiac hypertrophy.

Abstract Cardiac hypertrophy is a common pathological change accompanied by various cardiovascular diseases; however, its underlying mechanisms remain elusive. Mounting evidence indicates that long non-coding RNAs (lncRNAs) are novel transcripts involved in regulating multiple biological processes. However, little is known about their role in regulating cardiac hypertrophy. This study revealed a novel lncRNA4930473A02Rik (abbreviated as lncRNAA02Rik), which showed considerably increased expression in hypertrophic mouse hearts in vivo and angiotensin-II (Ang-II)-induced hypertrophic cardiomyocytes in vitro. Notably, lncRNAA02Rik knockdown partly ameliorated Ang-II induced hypertrophic cardiomyocytes in vitro and hypertrophic mouse heart function in vivo, whereas lncRNAA02Rik overexpression promoted cardiac hypertrophy in vitro. Furthermore, lncRNAA02Rik acted as a competing endogenous RNA by sponging miR-135a, while forced expression of lncRNAA02Rik could repress its activity and expression. Furthermore, forcing miR-135a overexpression exerted a significant protective effect against cardiac hypertrophy by inhibiting the activity of its downstream target TCF7, a critical member of Wnt signaling, and the protective effect could be reversed by AMO-135a. Luciferase assay showed direct interactions among lncRNAA02Rik, miR-135a, and TCF7. Altogether, our study demonstrated that lncRNAA02Rik upregulation could promote cardiac hypertrophy development via modulating miR-135a expression levels and TCF7 activity. Therefore, lncRNAA02Rik inhibition might be considered as a novel potential therapeutic strategy for cardiac hypertrophy.

RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.

The objective of this essay is to forge a more explicit link between the “visual turn” and the “practice turn” in entrepreneurship research. Specifically, we explore three key aspects of mobilizing visual methods for studying entrepreneurship-as-practice (EaP), i.e., data sources, collection strategies, and analytical perspectives, highlighting the important theoretical and empirical promises that visual methods hold for said research. This essay bears implications for researchers and educators working at the intersection of entrepreneurship research, the practice theory, and visual methods.

This research investigates the extent to which organizational change initiatives may lead to divergent patterns of sensemaking among organizational members. Drawing on the symbolic convergence theory, we performed an in-depth fantasy theme analysis of organization members’ rhetoric around an organizational change at a private university. Our analysis uncovers six fantasy themes and two corresponding fantasy types, which lead to no rhetorical vision. The lack of cognitive convergence between change initiators and change recipients suggests the inherent incompatibility between managerial and employee fantasies around organizational change, barring the exceptions of dual-responsibility change recipients (e.g., faculty members who also assume administrative responsibilities), who tend to adopt the change initiator rhetoric. Overall, this study informs our extant knowledge of change sensemaking with novel theoretical and methodological insights and bears implications for organizational change researchers and practitioners alike.

Abstract Background Modern dental education necessitates dynamic methodologies to foster critical thinking and teamwork skills, which might include case-based learning (CBL) and role play (RP). Objectives To evaluate the impact of the combined CBL and RP (CBL-RP) approaches on critical thinking and teamwork skills among dental students by comparing pre- and post-RP evaluation scores. Methods This pre-post intervention study was conducted at the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia. The study involved all 193 third-year dental students, who were organized into groups of 7–9 members to participate in four CBL sessions. Each CBL session consisted of a detailed case scenario, a pre-RP presentation preparation, a CBL-RP session facilitated by a trained instructor, and a post-RP presentation. Case scenarios included demographic data, chief complaints, medical and dental histories, social history, clinical images, radiographs, caries assessment, periodontal charts, and questions targeting specific intended learning outcomes and social factors impacting oral health. Students’ performances were evaluated pre- and post-RP using a standardized rubric focused on critical thinking and teamwork, with outcomes assessed through individual and collective scores. Outcomes were analysed using paired samples t-tests and repeated measures ANOVA. Results The study revealed significant improvements in total scores, combining critical thinking and teamwork, from pre- to post-RP evaluations across four sessions. Mean scores consistently increased post-RP (P

Introduction: India is committed to achieving universal health care for all by 2030. The objective of social marketing is to promote public health and its goal is to improve health for all, but there are some challenges like irregular availability, quality issue, inadequacy of marketing causes under- utilization of the government supplied health consumables. Objectives: Present study aims to find out the usage pattern and assess the perceived satisfaction level of beneficiaries of using various socially marketed health consumables at government settings and explore the perception of healthcare personnel regarding barriers to its usage in a rural area of India. Materials and Methods: A community-based, Mixed-Methods study (Convergent parallel design) was done in the service area of the Rural Health Unit and Training Centre (RHU&TC), Singur of Hooghly district, West Bengal, between January 2023 and December 2023, where the quantitative component was carried out by face-to-face interview among 150 beneficiary household respondents selected by two-stage cluster sampling; and qualitative component was done by 4 Key informant interviews (KII) among healthcare personnel (medical officer, public health nurse, pharmacist). Statistical data were analyzed by descriptive statistics using SPSS 16 version and Microsoft Excel for the quantitative part, and thematic analysis was done for the qualitative part. Institutional Ethics Committee clearance was obtained. Results: Ever use of government-supplied contraceptives like Chhaya (Ormeloxifene), Antara (Injectable contraceptive), emergency contraceptive pills, and intrauterine contraceptive devices (IUCD) was done by only 15.3%, 10.7%, 7.3%, 32% of eligible beneficiary households, respectively. The major reasons cited for irregular use were unawareness of availability of the products (Chhaya = 76.3%, Antara = 64.9%, EC pills = 46.7%), poor faith regarding quality (Male condom = 40%, Generic medicines = 70%), inadequate promotion (IUCD = 53.9%). The majority of users of male condoms (90%), IFA tablets (52.9%), ORS (51.1%), and generic medicines (55.7%) were not satisfied after using those products. Key informant interviews among healthcare personnel revealed avoidance of using modern contraceptive methods and frequent unavailability of some socially marketed health consumables were the predominant causes of reduced uptake of those products by beneficiaries. Conclusions: Proper social marketing strategies, adequate promotion, regular awareness campaigns, and tailored training of field healthcare workers are required to improve the acceptability, availability, and marketing of these health consumables.

Purpose A trauma team (TT) is reported to improve the management and polytraumas outcome. To assess the impact on, the decision-making process in the execution of surgical and interventional procedures, trauma patient results were examined before and after TT introduction. Methods This was a non-randomized single-center retrospective study of major trauma patients who accessed our level III university hospital Shock Room (SR) in the 20 months prior to the establishment of the TT (preTT group) and in the following 20 months (postTT group). Results There were 947 patients (418 preTT, 529 postTT) admitted in the SR due to a traumatic event. Comparing the 2 periods, a significant decreases in time spent in SR (p = 0.008), Sequential Organ Failure Assessment score in the Intensive Care Unit (p = 0.027), and estimated blood loss in Operating Room (p = 0.003) was observed. A significant increase was observed in the number of days of assisted ventilation (p < 0.001), the number of Damage Control Surgery procedures (p = 0.008), and non-operative managements for splenic and liver injuries (p = 0.004). Conclusion A significant change in the type of surgical procedures performed and increase in the number of non-operative managements were observed in the period following the implementation of the computed tomography; this was particularly evident in splenic trauma management where a complete alignment with the World Society of Emergency Surgery guidelines recommendations was reached. These results demonstrated the management of traumatic pathology with a dedicated TT represents the best approach for polytraumas.

Abstract Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generate a mouse model replicating the patients’ phenotypic defects, including retinal dystrophy and behavioral abnormalities. Our results reveal a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting potential functions in RNA and cilia metabolism. Transcriptomic analysis performed on mouse retina detect dysregulation in both gene expression and splicing activity, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. Proteomic analysis of mouse retina confirms the roles GPATCH11 plays in RNA processing, splicing, and transcription regulation, while also suggesting additional functions in synaptic plasticity and nuclear stress response. Our research provides insights into the diverse roles of GPATCH11 and identifies that the mutations affecting this protein are responsible for a recently characterized described syndrome.

Abstract In societies where education holds high significance and parental ambitions for their children’s academic achievements are profound, understanding the rationale behind parental school choice becomes crucial. This study aims to explore the question: Are Saudi parents rational in selecting their children’s schools? Through an in-depth analysis of preferences and decision-making factors, this research endeavors to shed light on the intricate dynamics influencing parental school choice within the Saudi Arabian context. To achieve this objective, semi-structured interviews were conducted with Saudi parents whose children were enrolled in private schools (K-12). The findings indicate that cultural or religious identity emerged as a predominant factor, encompassing elements such as gender segregation in schools, parental preference for English over Arabic language learning, and the emphasis on Islamic religious education. Additionally, accessibility factors such as the physical location of the school and school fees emerged as significant determinants of parental preferences for their children’s schools. Wellbeing emerged as a crucial factor in parental decision-making. Furthermore, certain academic considerations emerged as a primary influencing factor in Saudi parents’ school selection. These considerations included skills development, school pedagogy, school staff quality, and learning outcomes.

Despite the acknowledged merits of precision oncology (PO) and its increasing global implementation, its full potential for advancing care and prevention remains unrealized. The benefits are currently accessible to only limited patient segments because of multifaceted barriers. Successful implementation hinges on various factors—scientific complexities not limited to technical, clinical, regulatory, economic, administrative, and health care policy–related challenges. From building infrastructure to the associated costs, including research and development, testing, processing, and trained personnel, a lack of alignment persists. Administrative alignment with regulatory and payor acceptance is crucial. Health care policy must adapt to the ongoing shift from a one-size-fits-all treatment to a personalized approach. Without official endorsement of long-term gains over short-term costs and the health establishment's readiness for innovation, PO prospects, even in prosperous economies, may stagnate. Lower-income countries face exacerbated challenges, intensifying barriers to adoption. Nevertheless, growing awareness and utilization, driven by recognized potential for patients and public health, along with successful examples and advocacy, are progressively influencing policy for a more inclusive and beneficial approach to PO adoption.

Humans can perform movements in various physical environments and positions (corresponding to different experienced gravity), requiring the interaction of the musculoskeletal system, the neural system and the external environment. The neural system is itself comprised of several interactive components, from the brain mainly conducting motor planning, to the spinal cord (SC) implementing its own motor control centres through sensory reflexes. Nevertheless, it remains unclear whether similar movements in various environmental dynamics necessitate adapting modulation at the brain level, correcting modulation at the spinal level, or both. Here, we addressed this question by focusing on upper limb motor control in various gravity conditions (magnitudes and directions) and using neuromusculoskeletal simulation tools. We integrated supraspinal sinusoidal commands with a modular SC model controlling a musculoskeletal model to reproduce various recorded arm trajectories (kinematics and EMGs) in different contexts. We first studied the role of various spinal pathways (such as stretch reflexes) in movement smoothness and robustness against perturbation. Then, we optimised the supraspinal sinusoidal commands without and with a fixed SC model including stretch reflexes to reproduce a target trajectory in various gravity conditions. Inversely, we fixed the supraspinal commands and optimised the spinal synaptic strengths in the different environments. In the first optimisation context, the presence of SC resulted in easier optimisation of the supraspinal commands (faster convergence, better performance). The main supraspinal commands modulation was found in the flexor sinusoid's amplitude, resp. frequency, to adapt to different gravity magnitudes, resp. directions. In the second optimisation context, the modulation of the spinal synaptic strengths also remarkably reproduced the target trajectory for the mild gravity changes. We highlighted that both strategies of modulation of the supraspinal commands or spinal stretch pathways can be used to control movements in different gravity environments. Our results thus support that the SC can assist gravity compensation.

Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein–ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure–thermodynamics correlations for the novel inhibitors of CA IX is discussed – an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein–Ligand Binding Database to understand general protein–ligand recognition principles that could be used in drug discovery.

Introduction: Virtual reality (VR) is an emerging technology in fields including education and healthcare. A challenge for VR researchers is knowing which VR evaluation instruments exist, and which best align with their research objectives. Therefore, a systematic scoping review was conducted to identify and appraise questionnaires that evaluate VR. Methods: A scoping review across five scientific databases identified articles that described the development of questionnaires that evaluated VR. All identified articles were screened and data about the measured constructs, (psychometric) properties, and availability were extracted. Results: The initial search identified 4461 articles, 151 were full text screened, and 56 were included in the review. In total, seven constructs were measured to evaluate VR, of which presence (n = 26), user experience (n = 15) and motion sickness (n = 6) were most commonly used. However, these constructs were not always clearly defined, and measures of the same construct often differed in their content. Reliability was reported for 34 (59%) questionnaires, evaluations of validity were found in 42 (72%) questionnaires. Moreover, recommendations per construct on most optimal VR questionnaires were proposed. Discussion: A wide range of questionnaires used to evaluate VR were identified. Further, VR-related constructs were reviewed by comparing definitions, exploring questionnaire items, and examining their differences. Where relevant, constructs were divided (e.g. presence was divided into social, self, and spatial), and suitable definitions for each (sub-)construct were given. We provide recommendations for a structured approach of the development of measures to evaluate VR alongside priority areas where new measures are most sorely needed.

سعى البحث الحالي للكشف عن درجة تطبيق متطلبات التعليم الريادي في برنامج الدراسات العليا في كلية التربية برأي أفراد هيئة التدريس، وتعرف الفروق تيعاً للجنس والقسم والمرتبة العلمية وسنوات الخبرة. وقد طبق البحث على أفراد العينة كلها مؤلفة من (53) عضو هيئة تدريسية في كلية التربية جامعة تشرين، اتبع البحث المنهج الوصفي، واستخدم البحث مقياس متطلبات التعليم الريادي من إعداد الباحث. وأظهرت النتائج أن مستوى تطبيق متطلبات التعليم الريادي في برنامج الدراسات العليا في كلية التربية برأي أفراد هيئة التدريس كان متوسطاً في درجته الكلية وعلى كل من محوري(المتطلبات التشريعية والادارية، المتطلبات الفنية والبشرية)، بينما جاء مستوى تطبيق محور المتطلبات المالية والتجهيزية منخفضاً، كما تبين عدم وجود فرق برأي أعضاء الهيئة التدريسية بدرجة توافر متطلبات التعليم الريادي في برنامج الدراسات العليا تبعاً لمتغيرات (الجنس والقسم الذي يتبع له المدرس)، بينما تبين وجود فروق بينهم تبعاً للمرتبة العلمية لصالح مرتبة أستاذ ومدرس متأصل، كما ظهرت فروق بينهم تبعاً لسنوات الخبرة لصالح سنوات الخبرة الأكثر من ست سنوات.

Abstract Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.

Based on the best-track dataset from the Shanghai Typhoon Institute/China Meteorological Administration, the paper provides a comprehensive summary and analysis of tropical cyclone (TC) activities in the Western North Pacific (WNP) and the South China Sea (SCS) for 2022. Using the historical climatology from 1951 to 2020, the anomalous conditions during 2022 in TC frequency, origin locations, tracks, intensity, and duration for the entire ocean basin as well as landfall events in China are examined. Results show that the overall TC frequency is slightly lower than normal, but the multiple TC events have a very high frequency of occurrence. Origin locations of TCs, which mark the starting points of their paths, show a large westward and northward deviation from climatology. Around 40% of the named TCs exhibit a shift in their direction of movement from westerly to easterly. Additionally, comparisons of the means, medians, upper and lower quartiles all indicate that the intensity of TCs in 2022 is generally lower than the climatology, with the duration of TCs at tropical storm intensity or above being shorter than usual. A notable observation is the fewer incidence of TC landfalls in China, but with a geographical concentration in Guangdong Province. These anomalous annual TC activities are influenced by related atmospheric and oceanic environmental conditions modulated by multi-scale climate variability. The findings provide useful information for enhancing disaster mitigation strategies in the Asia-Pacific region.

Abstract Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82–0.84) and a balanced accuracy of 0.78 (95% CI 0.77–0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40–0.74). Quantitative PCR validated LEF1-AS1’s adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management.

BACKGROUND: In 2006, the World Health Organization (WHO) introduced new growth standards based on data derived globally from optimally nourished breastfed infants. The aim of this study was to assess the effects of implementing WHO growth standards on the growth patterns of Jordanian infants. In addition, it was to ascertain the necessity of establishing country-specific growth standards and charts tailored to Jordanian infants. MATERIALS AND METHODS: The data of 102,846 infants (50.1% boys, 49.9% girls) aged 0–24 months, from 115 primary healthcare centers across the country were retrieved from a National E-health Program. Weight and length measurements were analyzed, and age- and sex-specific z-scores were calculated relative to the WHO growth standards. Data was analyzed using SPSS version 26. Mann–Whitney U test was performed to determine significant differences between the measurements for boys and girls in terms of age, length, and weight. RESULTS: Jordanian infants exhibited significantly shorter length-for-age measurements than WHO standards with mean z-scores of −0.56 and −0.38, for boys and girls, respectively. Weight-for-age measurements showed a good fit and were comparable to the WHO growth standards for boys (mean z score = −0.05) and girls (mean z score = 0.04). Notably, Jordanian infants displayed higher weight-for-length measurements, with mean z-scores of 0.51 for boys and 0.47 for girls. CONCLUSION: The availability of Jordanian-specific growth standards will improve the accuracy of assessing infant growth and enhance the monitoring and evaluation of their health and development.

Abstract Background Helsmoortel–Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. Results The clinical presentation of the patient was representative of the Helsmoortel–Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein–protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. Conclusion This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel–Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel–Van der Aa syndrome and holds promise as a new therapeutic target. Graphical abstract

Abstract Coronavirus disease 2019 (COVID‐19) has been a major public health burden. We hypothesised that circulating extracellular vesicles (cEVs), key players in health and disease, could trace the cell changes during COVID‐19 infection and recovery. Therefore, we studied the temporal trend of cEV and inflammatory marker levels in plasma samples of COVID‐19 patients that were collected within 24 h of patient admission (baseline, n = 80) and after hospital discharge at day‐90 post‐admission (n = 59). Inflammatory markers were measured by standard biochemical methods. cEVs were quantitatively and phenotypically characterized by high‐sensitivity nano flow cytometry. In patients recovered from COVID‐19 lower levels of inflammatory markers were detected. cEVs from vascular (endothelial cells) and blood (platelets, distinct immune subsets) cells were significantly reduced at day‐90 compared to admission levels, a pattern also observed for cEVs from progenitor, perivascular and epithelial cells. The best discriminatory power for COVID‐19 severity was found for inflammatory markers lactate dehydrogenase and neutrophil‐to‐lymphocyte ratio and for granulocyte/macrophage‐released CD66b+/CD68+‐cEVs. Albeit inflammatory markers were good indicators of systemic inflammatory response and discriminators of COVID‐19 remission, they do not completely reveal cell stress and organ damage states. cEVs reaching baseline pre‐infection levels at 90 days post‐infection in recovered patients discriminate parental cells affected by disease.

هدف البحث إلى تقصي مستوى التفكير الناقد ومستوى التحصيل في مادة الدراسات الاجتماعية لدى تلاميذ الصف الخامس الأساسي, ثمّ تعرّف العلاقة بينهما. ولتحقيق هذا الهدف استخدم المنهج الوصفي, وتمّ إعداد اختبار " التفكير الناقد" و"اختبار تحصيلي في مادة الدراسات الاجتماعية" وبعد التأكد من صدق وثبات الاختبارين طبقا على عينة قوامها(240) تلميذاً وتلميذةً من تلاميذ الصف الخامس الأساسي في مدينة حلب للعام الدراسي 2023/2024. وأظهرت النتائج أن مستوى التفكير الناقد لدى أفراد عينة البحث كان متوسطاً بالنسبة للدرجة الكليّة للاختبار ولكلّ بعد من أبعاده المتمثلة ﺑ (تعرّف الافتراضات, التفسير, الاستنتاج, الاستنباط, تقييم الحجج), كما أظهرت النتائج أن مستوى التحصيل في مادة الدراسات الاجتماعية كان متوسطاً بالنسبة إلى الدرجة الكلية وبالنسبة إلى مستويات بلوم الدنيا, بينما كان مستوى التحصيل منخفضاً بالنسبة إلى مستويات بلوم العليا , كما تبين وجود علاقة ارتباطية بين درجات التلاميذ على اختبار التفكير الناقد ودرجاتهم على الاختبار التحصيلي, وهذه العلاقة طردية.

Introduction: Self-directed learning (SDL) is the process in which individuals take the initiative and learning environment involves all other aspects of the institute. Good SDL ability is the foundation of lifelong learning. Students’ perception of the educational environment plays a subtle role in learning and contributes to learning input and students’ achievement. Self- directed learning is integral to public health teaching. Objectives: To assess the perceptions of learning environment and self-directed learning readiness and association between the two among public health researchers and also to elicit the factors associated with SDLRS. Method: A cross-sectional study was conducted from July to December 2023 in a public health institute in Kolkata. A total of 102 participants across five courses were selected by Complete Enumeration method and their self-directed learning readiness (SDLRS) and perceptions of learning environment were assessed using a self-administered questionnaire. The data was analysed in SPSS, version 16. Ethical approval was taken. Results: The mean age of the study participants was 26.7 years and 64.7% of the study participants were from MBBS background. The median academic hours was 18 hours per week, 37.3% of the participants were studying in the institute for less than 6 months and 20.6% for more than 24 months. The overall perception of learning environment was more positive than negative. There was significant positive correlation between SDLRS and Learning Environment (Spearman’s rho=0.281, p=0.004). Age (p=0.015) and prior academic qualification (p=0.016) were significantly associated with SDLRS. Conclusion: SDLRS was associated with positive Learning Environment. The overall perception of SDLRS was average and the SDL ability improved with duration of study in the institute and deteriorated with age of the study participants.

Cooperative communications is a core research area in wireless vehicular networks (WVNs), thanks to its capability to provide a certain degree of fading mitigation and to improve spectral efficiency. In a cooperative scenario, the intercept probability of the system can be reduced by optimizing the relay selection scheme in order to select the optimal relay from a set of available relays for data transmission. However, due to the mobility of WVNs, the best relay is often selected in practice based on outdated channel state information (CSI), which in turn affects the overall system performance. Therefore, there is a need for a robust relay selection scheme (RSS) that guarantees a satisfactory overall achievable performance in the presence of an outdated CSI. Motivated by this and considering the advantageous features of autoregressive moving average (ARMA), the proposed contribution models a cooperative vehicular communication scenario with relay selection as a Markov decision process (MDP) and proposes two deep Q-networks (DQNs), namely DQN-RSS and DQN-RSS-ARMA. In the proposed framework, two deep reinforcement learning (RL)-based RSS are trained based on the intercept probability, aiming to select the optimal vehicular relay from a set of multiple relays. We then compare the proposed RSS with the conventional methods and evaluate the performance of the network from the security point of view. Simulation results show that DQN-RSS and DQN-RSS-ARMA perform better than conventional approaches, as they reduce intercept probability by approximately 15% and 30%, respectively, compared to the standard ARMA approach.

In power-constrained wireless networks, extending network lifespan can be achieved through effective energy harvesting techniques. Developing energy-efficient routing protocols in such networks is complex due to the unstable and unpredictable harvested energy. In this regard, reconfigurable Intelligent Surfaces (RIS), capable of manipulating the RF signals, offer enhanced energy harvesting, which in turn minimizes the nodes’ battery recharging time (BRT). Our study presents a novel RIS-assisted routing protocol for multi-hop energy harvesting-based wireless networks. The protocol assigns channels to each hop on the chosen path. It incorporates a rate calculation algorithm that takes into consideration the harvested power, BRT, and channel conditions. More specifically, it assigns a specific rate to every available channel, taking into account the energy available at each node, the estimated time required for battery recharging, and the link status between nodes. By selecting the highest rate per hop, the protocol enhances network throughput while considering energy limits and channel quality. The proposed approach is evaluated and compared with the benchmark, the Min hop scheme, using MATLAB simulations, demonstrating its superior performance.

The rise of the Internet of Things (IoT), marked by unprecedented growth in connected devices, has created an insatiable demand for supplementary computational and communication resources. The integration of Unmanned aerial vehicles (UAVs) within IoT ecosystems presents a promising avenue to surmount these obstacles, offering enhanced network coverage, agile deployment capabilities, and efficient data gathering from geographically challenging locales. UAVs have been recognized as a compelling solution, offering extended coverage, flexibility, and reachability for IoT networks. Despite these benefits, UAV technology faces significant challenges, including limited energy resources, the necessity for adaptive responses to dynamic environments, and the imperative for autonomous operation to fulfill the evolving demands of IoT networks. In light of this, we introduce an innovative UAV-assisted data dissemination framework that aims to minimize the total energy expenditure, considering both the UAV and all spatially-distributed IoT devices. Our framework addresses three interconnected subproblems: device classification, device association, and path planning. For device classification, we employ two distinct types of deep reinforcement learning (DRL) agents—Double Deep Q-Network (DDQN) and Proximal Policy Optimization (PPO)—to classify devices into two tiers. To tackle device association, we propose an approach based on the nearest-neighbor heuristic to associate Tier 2 devices with a Tier 1 device. For path planning, we propose an approach that utilizes the Lin-Kernighan heuristic to plan the UAV’s path among the Tier 1 devices. We compare our method with three baseline approaches and demonstrate through simulation results that our approach significantly reduces energy consumption and offers a near-optimal solution in a fraction of the time required by brute force methods and ant colony heuristics. Consequently, our framework presents an efficient and practical alternative for energy-efficient data dissemination in UAV-assisted IoT networks.

This study aimed to assess and evaluate the canal shaping ability of two different Ni-Ti rotary systems, Vortex Blue (VB) and TruNatomy (TN), using micro-computed tomography in extracted premolars. A total of 20 extracted bifurcated maxillary first premolars with two separate canals were randomly divided into two groups and prepared with either VB 35/0.04 (Dentsply Maillefer, Ballaigues, Switzerland) or TN Medium 36/0.03 (Dentsply Sirona). Pre- and post-instrumentation micro-CT scans were analyzed to measure the following parameters: percentage of untouched canal surface area, changes in canal surface area, changes in canal volume, structural model index (SMI), changes in canal angulation, changes in dentin thickness, transportation, and centering ability. Statistical analysis was performed with a significance level set at p-value < 0.05. Both VB and TN files showed a significant increase in the basic canal geometry parameters including canal surface area and canal volume. Both file systems showed no significant changes in SMI or dentin thickness after canal instrumentation (p > 0.05). Some degree of canal transportation and a similar centering ability ratio with no significant difference were observed in both file systems (p > 0.05). TN files showed less pre-cervical dentin removal when compared to VB files. A significant difference was found in the TN group regarding the dentin removal between coronal and apical thirds (p = 0.03). Both VB and TN files produced comparable root canal preparation with no considerable shaping mishaps and errors. Both files showed minimum canal transportation and minimum straightening of the canal curvature. TN files removed less pre-cervical dentin than apical dentin.