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Abstract During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.

Abstract A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. Using a forward genetic screen, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Trans-Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells, leading to a decrease in antimicrobial peptides and more penetrable mucus layer. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficient colonocytes have a common deficiency of several critical glycosylation enzymes. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo.

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.

Myosin ID (MYO1D) is a member of the class I myosin family. We screened 48,649 third generation (G3) germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). We found and validated mutations in Myo1d as a cause of increased susceptibility to DSS-induced colitis. MYO1D is produced in the intestinal epithelium, and the colitis phenotype is dependent on the nonhematopoietic compartment of the mouse. Moreover, MYO1D appears to couple cytoskeletal elements to lipid in an ATP-dependent manner. These findings demonstrate that MYO1D is needed to maintain epithelial integrity and protect against DSS-induced colitis.

During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens. Endosomal recycling relies on SNX17 to transport membrane proteins via Retriever. Here, authors reveal the mechanisms of SNX17 autoinhibition and its interaction with Retriever, uncovering a broader family of factors with similar binding strategies. [ABSTRACT FROM AUTHOR]

In order to keep up with the developing student profile in this century, the competencies of teachers and pre-service teachers in technology should be increased; both groups should follow the new developments on the agenda and be up to date. The aim of this study is to examine the use of ChatGPT, one of the generative artificial intelligence tools, by pre-service mathematics teachers and to present a study. Pre-service mathematics teachers in the 4th grade at a state university were asked to prepare a lesson plan in accordance with the 5E learning model. The data of the study were collected by recording this process. The study is a qualitative study by nature. Case study design was used in the study. When the findings of the study were examined, it was concluded that the pre-service teachers made changes in the lesson plans presented by ChatGPT in the sections of duration, number of activities, type of activities, expansion/change in the stages of the method used, methods and techniques used in the lesson plan, integrating technology. When the data obtained during the study are analyzed, it is seen that pre-service teachers' competencies in using ChatGPT are not strong. [ABSTRACT FROM AUTHOR]

A20 is an anti-inflammatory protein linked to multiple human autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20(OTU) proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling.

Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.

Zinner syndrome (ZS) was first described by Zinner in 1914. This condition includes unilateral renal agenesis, ipsilateral seminal vesicle cyst, and ejaculatory duct obstruction. ZS treatments ranging from medical drug therapy to laparoscopic interventions have been investigated in the literature. A 21-year-old patient presented with scrotal pain after ejaculation. The diagnosis was Zinner’s syndrome, and the patient underwent transperitoneal laparoscopic excision of the left seminal vesicle cyst. After 2 years, transurethral ejaculatory duct resection (TUR-ED) was performed at a single center because of symptomatic dilatation in the seminal vesicles. The patient’s 1-year urological follow-up after TUR-ED remained normal. This presentation is a case report of a single patient and two cases that are rare in the literature. Cyst aspiration and seminal cyst excision may be considered as first-line treatment options, but the possibility of recurrence should not be forgotten. Even if seminal cyst excision is performed, it should be kept in mind that TUR-ED may be required in the future.

Web services play an important role in our daily lives. They are used in a wide range of activities, from online banking and shopping to education, entertainment and social interactions. Therefore, it is essential to ensure that they are kept as secure as possible. However – as is the case with any complex software system – creating a sophisticated software free from any security vulnerabilities is a very challenging task. One method to enhance software security is by employing static code analysis. This technique can be used to identify potential vulnerabilities in the source code before they are exploited by bad actors. This approach has been instrumental in tackling many vulnerabilities, but it is not without limitations. Recent research suggests that static code analysis can benefit from the use of large language models (LLMs). This is a promising line of research, but there are still very few and quite limited studies in the literature on the effectiveness of various LLMs at detecting vulnerabilities in source code. This is the research gap that we aim to address in this work. Our study examined five notable LLM chatbot models: ChatGPT 4, ChatGPT 3.5, Claude, Bard/Gemini1, and Llama-2, assessing their abilities to identify 104 known vulnerabilities spanning the Top-10 categories defined by the Open Worldwide Application Security Project (OWASP). Moreover, we evaluated issues related to these LLMs’ false-positive rates using 97 patched code samples. We specifically focused on PHP vulnerabilities, given its prevalence in web applications. We found that ChatGPT-4 has the highest vulnerability detection rate, with over 61.5% of vulnerabilities found, followed by ChatGPT-3.5 at 50%. Bard has the highest rate of vulnerabilities missed, at 53.8%, and the lowest detection rate, at 13.4%. For all models, there is a significant percentage of vulnerabilities that were classified as partially found, indicating a level of uncertainty or incomplete detection across all tested LLMs. Moreover, we found that ChatGPT-4 and ChatGPT-3.5 are consistently more effective across most categories, compared to other models. Bard and Llama-2 display limited effectiveness in detecting vulnerabilities across the majority of categories listed. Surprisingly, our findings reveal high false positive rates across all LLMs. Even the model demonstrating the best performance (ChatGPT-4) notched a false positive rate of nearly 63%, while several models glaringly under-performed, hitting startlingly bad false positive rates of over 90%. Finally, simultaneously deploying multiple LLMs for static analysis resulted in only a marginal enhancement in the rates of vulnerability detection. We believe these results are generalizable to most other programming languages, and hence far from being limited to PHP only.

Objective: To examine the impact of digital parenting awareness (DPA) levels on problematic media use (PMU) among children. Method: This cross-sectional study was conducted with children between the ages of 7-11 who admitted to the family medicine outpatient clinic of a tertiary hospital between 09.06.2022 and 08.12.2022, and met the inclusion criteria for themselves and their parents. Data were obtained through the Patient Information Form, Digital Parenting Awareness Scale (DPAS), and Problematic Media Use Measure-Short Form (PMUM-SF) administered to the parents. Results: A total of 301 children, with an average age of 8.21±1.13 years and 174 (57.8%) girls, were included in the study. Most children had access to televisions (80.1%), mobile phones (67.4%), and tablets (34.6%) during the day. The percentage of those who spent ≥5 hours in front of the screen was 3.7% on weekdays and 14.6% on weekends. The mean PMUM-SF score was 17.37±7.40. The mean scores were 7.25±2.41 for Being Negative Model (NM), 9.05±3.34 for Digital Negligence (DN), 15.96±3.29 for Efficient Use (EU) and 15.09±3.61 for Protection From Risks (PR). There was a positive relationship between PMU, NM, and DN, but a negative relationship between EU and PR (p

Prognostic nutritional index (PNI), consisting of inflammatory-nutritional parameters, has been investigated in terms of outcomes and renal function in patients with coronary artery disease. The objective of this study is to assess the predictive power of the PNI in predicting the risk for developing contrast-associated acute kidney injury (CA-AKI), an important complication following coronary angiography in patients with non-ST-elevation myocardial infarction (NSTEMI). The study population (336 patients with the diagnosis of NSTEMI) was divided into two groups: patients with CA-AKI and patients without CA-AKI. The mean age of the whole population was 62.0 ± 12.7 (21–95) years. CA-AKI was detected in 68 (20%) patients. Prognostic nutritional index values were significantly (P <.001) lower in the CA-AKI (+) group. Low PNI values (cutoff < 48.5%) were independent predictors of CA-AKI with Odds ratio (OR):.913, 95% confidence interval (CI):.866–.962, P :.001, with a sensitivity 70.6% and specificity 69.4%. Prognostic nutritional index seems to be an easily assessable and promising scoring system that can be used in clinical practice for predicting the risk of developing CA-AKI. [ABSTRACT FROM AUTHOR]

A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. Using a forward genetic screen, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Trans-Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells, leading to a decrease in antimicrobial peptides and more penetrable mucus layer. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficient colonocytes have a common deficiency of several critical glycosylation enzymes. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo. Increased susceptibility to gastrointestinal infections and colitis can be driven by a failure to maintain intestinal homeostasis. Here, using a forward genetic screen, Song et al. identify and characterise the role of TVP23B in Paneth cell and goblet cell function, and its impact on colitis. [ABSTRACT FROM AUTHOR]

We aimed to determine the quality of AI-generated (ChatGPT-4 and Claude 3) Script Concordance Test (SCT) items through an expert panel. We generated SCT items on abdominal radiology using a complex prompt in large language model (LLM) chatbots (ChatGPT-4 and Claude 3 (Sonnet) in April 2024) and evaluated the items’ quality through an expert panel of 16 radiologists. Expert panel, which was blind to the origin of the items provided without modifications, independently answered each item and assessed them using 12 quality indicators. Data analysis included descriptive statistics, bar charts to compare responses against accepted forms, and a heatmap to show performance in terms of the quality indicators. SCT items generated by chatbots assess clinical reasoning rather than only factual recall (ChatGPT: 92.50%, Claude: 85.00%). The heatmap indicated that the items were generally acceptable, with most responses favorable across quality indicators (ChatGPT: 71.77%, Claude: 64.23%). The comparison of the bar charts with acceptable and unacceptable forms revealed that 73.33% and 53.33% of the questions in the items can be considered acceptable, respectively, for ChatGPT and Claude. The use of LLMs to generate SCT items can be helpful for medical educators by reducing the required time and effort. Although the prompt provides a good starting point, it remains crucial to review and revise AI-generated SCT items before educational use. The prompt and the custom GPT, “Script Concordance Test Generator”, available at https://chatgpt.com/g/g-RlzW5xdc1-script-concordance-test-generator, can streamline SCT item development.

Probiotics are live microorganisms that provide health benefits to the host when taken in adequate amounts. Hesperidin is a phenolic compound found in banana fruit, lemon fruit, and lemon peel. It exhibits anti-inflammatory, anti-oxidative, and anti-cancer activities. Although these compounds are present in the gastrointestinal tract (GIT), their synbiotic interaction on the GIT is not well understood. This study aims to investigate the effects of hesperidin on the probiotic properties of Lactobacillus acidophilus LA-5 (LA-5) and the impact of their synbiotic interaction on the cancer cell line HT-29. Results showed that hesperidin did not negatively affect the auto-aggregation, adhesion, and antioxidant capacity of LA-5. LA-5 grown with hesperidin exhibited greater resistance to pepsin and bile salt compared to LA-5 alone. Furthermore, in vitro cancer studies indicated that bacteria grown in the presence of hesperidin may increase caspase-3 activity in HT-29 cells and thus induce apoptosis in this way. This study suggests that hesperidin may enhance and contribute to the probiotic properties of LA-5. Consequently, LA-5 grown with hesperidin may exert more beneficial effects on the host.

The use of automatic item generation (AIG) methods offers potential for assessing clinical reasoning (CR) skills in medical education, a critical skill combining intuitive and analytical thinking. In preclinical education, these skills are commonly evaluated through written exams and case-based multiple-choice questions (MCQs), which are widely used due to the high number of students, ease of standardization, and quick evaluation. This research generated CR-focused questions for medical exams using two primary AIG methods: template-based and non-template-based (using AI tools like ChatGPT for a flexible approach). A total of 18 questions were produced on ordering radiologic investigations for abdominal emergencies, alongside faculty-developed questions used in medical exams for comparison. Experienced radiologists evaluated the questions based on clarity, clinical relevance, and effectiveness in measuring CR skills. Results showed that ChatGPT-generated questions measured CR skills with an 84.52% success rate, faculty-developed questions with 82.14%, and template-based questions with 78.57%, indicating that both AIG methods are effective in CR assessment, with ChatGPT performing slightly better. Both AIG methods received high ratings for clarity and clinical suitability, showing promise in producing effective CR-assessing questions comparable to, and in some cases surpassing, faculty-developed questions. While template-based AIG is effective, it requires more time and effort, suggesting that both methods may offer time-saving potential in exam preparation for educators.

IntroductionThe immune system is an intricate network of cellular components that safeguards against pathogens and aberrant cells, with CD4+ T cells playing a central role in this process. Human space travel presents unique health challenges, such as heavy ion ionizing radiation, microgravity, and psychological stress, which can collectively impede immune function. The aim of this research was to examine the consequences of simulated space stressors on CD4+ T cell activation, cytokine production, and gene expression.MethodsCD4+ T cells were obtained from healthy individuals and subjected to Fe ion particle radiation, Photon irradiation, simulated microgravity, and hydrocortisone, either individually or in different combinations. Cytokine levels for Th1 and Th2 cells were determined using multiplex Luminex assays, and RNA sequencing was used to investigate gene expression patterns and identify essential genes and pathways impacted by these stressors.ResultsSimulated microgravity exposure resulted in an apparent Th1 to Th2 shift, evidenced on the level of cytokine secretion as well as altered gene expression. RNA sequencing analysis showed that several gene pathways were altered, particularly in response to Fe ions irradiation and simulated microgravity exposures. Individually, each space stressor caused differential gene expression, while the combination of stressors revealed complex interactions.DiscussionThe research findings underscore the substantial influence of the space exposome on immune function, particularly in the regulation of T cell responses. Future work should focus expanding the limited knowledge in this field. Comprehending these modifications will be essential for devising effective strategies to safeguard the health of astronauts during extended space missions.ConclusionThe effects of simulated space stressors on CD4+ T cell function are substantial, implying that space travel poses a potential threat to immune health. Additional research is necessary to investigate the intricate relationship between space stressors and to develop effective countermeasures to mitigate these consequences.

Abstract Background For renal stones > 20 mm, percutaneous nephrolithotomy (PNL) offers the best stone clearance rates with acceptable complication rates. This study aimed to compare the efficiency of high-power holmium YAG laser and ballistic lithotripsy during mini-PNL. Methods Data from 880 patients who underwent mini-PNL for renal stones was investigated retrospectively. The study utilized propensity score matching to create two groups: laser lithotripsy (n = 440) and ballistic lithotripsy (n = 440). The groups were matched based on stone size, Guy’s stone score, and stone density. The main objectives of the study were to assess the stone-free rate (SFR), duration of surgery, and complication rates. Results The average age of the population was 51.4 ± 7.1 years, with a mean stone size of 28.6 ± 8.3 mm and a mean stone density of 1205 ± 159 HU. There were no significant differences between the groups. The SFRs of the laser lithotripsy and ballistic lithotripsy were 92.5% and 90.2%, respectively (p = 0.23). The laser lithotripsy group had a notably shorter surgery time (40.1 ± 6.3 min) compared to the ballistic lithotripsy group (55.6 ± 9.9 min) (p = 0.03). Complication rates were similar (p = 0.67). Conclusions Our study shows that a high-power holmium YAG laser provides quicker operation time compared to ballistic lithotripsy. However, ballistic lithotripsy is still an effective and safe option for stone fragmentation during mini-PNL. In places where a high-power holmium YAG laser is not available, ballistic lithotripters are still a safe, effective, and affordable option for mini-PNL.

Rat ve fareler bilimsel çalışmalarda yaygın olarak kullanılan laboratuvar hayvanlarıdır. Rat ve farelerin bulundurulduğu ortam hayvanların yaşam alanı kriterlerine uygun olmalıdır. Hayvan sağlığı ve refahının sağlanamaması durumunda bilimsel çalışmalar etkilenir ve yanlış sonuçlar elde edilir. Yaşam alanı kriterlerinin ilk basamağı tesis tasarımıdır. Tesis rat ve fareler için uygun olacak şekilde tasarlanmalıdır. Rat ve farelerin bulundurulduğu odalar Laboratuvar Hayvanlarının Bakımı ve Kullanımı Kılavuzu'nun yönergelerine uygun olacak şekilde düzenlenmelidir. Oda içine yerleştirilecek kafesler çalışma amacına göre belirlenmekle birlikte kolay temizlenebilir, kaçmaya karşı korumalı olmalıdır. Çalışma için gerekli olmadığı sürece tel kafesler yerine katı tabanlı olan kafesler tercih edilmelidir. Kafes boyutları hayvan popülasyonuna göre belirlenmelidir. Sıcaklık, nem, hava hareketi, aydınlatma, sanitasyon ve gürültü, yem su ve altlık araştırma sonuçlarını etkileyen çevresel faktörlerdir. Rat ve farelerin bulunduğu ortam fizyolojilerine uygun sıcaklık ve nem derecesinde olmalı, Etkili bir havalandırma ve uygun bir fotoperiyod döngüsü sağlanmalı ve gürültüden uzak olmalıdır. Ayrıca sağlığa elverişli koşulların sürdürülmesi ve dezenfeksiyon için etkili bir sanitasyon belirlenmelidir. Yem, su ve altlık materyali de hayvan refahını etkileyen önemli çevresel faktörlerdir. Yem fare ve ratların ihtiyacına göre belirlenmeli, temiz su sağlanmalı ve en uygun altlık malzemesi kullanılmalıdır.

An important development task for university students is to complete their education and join the labour market. Therefore, understanding and exploring students' concerns about getting a job seems to be a noteworthy area in supporting their career development. The present study aims to explore the concerns of university students about employment. Semi-structured focus group interviews were conducted with 16 third- and fourth-year Turkish university students (8 females and 8 males) from various departments. The participants responded to questions such as what they thought about finding a job after graduation and how individual and contextual factors affected their concerns. The data were analyzed using thematic analysis in accordance with the Ecological Theory framework and The Systems Theory Framework of career development. Consequently, employment anxiety appeared in the factors that were individual, close-circle, labor market, and systematic. Further, findings showed that participants also had concerns about underemployment as well as unemployment. In light of the findings, implications and recommendations regarding career counseling and career development were discussed.