Bilkent University

Ionic motion at the interlamellar space in layered materials can provide superior properties in electrochemical energy storage, neuromorphic computing, and ion-mediated charge transport. Herein, we demonstrate the synthesis of ultra-thin,...

On the upper reaches of the Tigris and Euphrates, archaeologists encounter evidence that challenges conventional understand- ings of early state formation as a transition from ‘small-scale, egalitarian’ to ‘large-scale, stratified’ societies. One such location is the Early Bronze Age cemetery of Başur Höyük, which presents evidence of grand funerary rituals—including ‘retainer burials’ and spectacular deposits of metallic wealth—in an otherwise small-scale, egalitarian setting. A further, puzzling feature of this cemetery is the preponderance of teenagers in the richest tombs. Here we describe the combined results of archaeological and anthropological analysis at Başur Höyük, including ancient DNA, and consider the challenges they pose to traditional accounts of early state formation.

A dysplastic nevus (DN) is an acquired melanocytic nevus that displays clinical and histological features similar to malign melanoma (MM). This study aims to evaluate the demographic and clinical characteristics of DN and primary cutaneous MM, as well as assess the accuracy of pre-biopsy diagnoses. We retrospectively analyzed 206 histopathologically confirmed cases of DN (n = 185) and MM (n = 21) from 159 patients at a tertiary care center. The biopsy samples had been sent from both dermatology and other surgical departments. The study included 21 patients with MM and 139 with DN; one patient had both conditions. The mean age was 60.6 ± 15.9 years for MM patients and 34.7 ± 14.9 years for DN patients, both with a slight male predominance. Melanomas were predominantly on the face (42.9%), whereas DN lesions were mostly on the trunk (76.8%). Breslow thickness analysis showed 33.3% of MM tumors were < 1 mm and 28.6% were > 4 mm. In 90.5% of MM cases and 71.4% of DN cases, preliminary diagnoses of MM and/or DN were noted on pathology request forms. Overall, pre-biopsy diagnoses were consistent with final diagnoses in 73.3% of the 206 lesions. Diagnostic accuracy was higher in dermatology compared to other surgical departments (85.8% vs. 50%, p <.00001) and was better for trunk and feet locations compared to unspecified areas (p = .023 and p = .044, respectively). The study highlights the need for dermatology consultation before excising nevi or suspicious lesions and emphasizes early melanoma detection. Despite the small sample size, it underscores the importance of enhanced screening methods and awareness campaigns.

In this study, we aimed to present the clinical and radiologic outcomes of patients with chronic AC joint separation who underwent an autograft and double endobutton application. In addition, we examined the results of patients who had coracoclavicular (CC) ligament reconstruction using autogenous hamstring tendon, without the use of implants. A retrospective evaluation was conducted on 21 patients who underwent CC ligament complex reconstruction surgery for chronic AC joint separation. All patients were evaluated in our hospital using history taking, clinical examination, radiologic evaluation, Constant, Taft and Acromioclavicular Joint Instability (ACJI) scores. The postoperative follow-up period had a mean of 37.3 months (min 15 months–max 68 months). The results of the study revealed significant improvements in clinical scores post-surgery among the 21 male patients with chronic AC joint separation. Specifically, the Constant, Taft, and ACJI scores all showed statistically significant increases from preoperative to postoperative assessments (p <0.001). Radiologically, the coracoclavicular distance in the operated joints significantly reduced to near-normal values compared to the preoperative measurements, indicating successful surgical outcomes. This study shows that reconstruction with autogenous graft in chronic AC separation cases yields successful results in terms of functional scores and radiologic measurements. Level 4, Treatment Studies.

Transforming growth factor‐β (TGF‐β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. Despite provoking senescence‐associated growth arrest in epithelial HCC cells, elevated TGF‐β activity paradoxically correlates with increased aggressiveness and poor prognosis in advanced tumors. Whether the transition between these dichotomous functions involves modulation of the senescence phenotype during disease progression remains elusive. Exploiting the epithelial HCC cell line Huh7 as a robust model, we demonstrate that chronic exposure to TGF‐β prompts escape from Smad3‐mediated senescence, leading to the development of TGF‐β resistance. This altered state is characterized by an optimal proliferation rate and the acquisition of molecular and functional traits of less‐differentiated mesenchymal cells, coinciding with differential growth capacity in 2D and 3D culture conditions, epithelial‐to‐mesenchymal transition (EMT), and increased invasiveness in vitro, and metastasis in vivo. Mechanistically, resistant cells exhibit defective activation and nuclear trafficking of Smad molecules, particularly Smad3, as ectopic activation of the TGF‐β/Smad3 axis is able to reinstate TGF‐β sensitivity. An integrated transcriptomic landscape reveals both shared and distinct gene signatures associated with senescent and TGF‐β resistant states. Importantly, genetic ablation and molecular studies identify microtubule affinity regulating kinase 1 (MARK1) and glutamate metabotropic receptor 8 (GRM8) as critical modulators of the resistance phenomenon, potentially by impairing spatiotemporal signaling dynamics of Smad activity. Our findings unveil a novel phenomenon wherein epithelial HCC cells may exploit senescence plasticity as a mechanism to oppose TGF‐β anti‐tumor responses and progress towards more aggressive HCC phenotypes.

Purpose Infective endocarditis (IE) is a evolving disease with a shifting epidemiology and disease burden over time. This study aimed to compare the epidemiological and clinical aspects of IE over three time periods across eleven years. Methods This was a retrospective cohort, multicenter study conducted in Türkiye, comparing three periods: 2013–2016, 2017–2020, and 2021–2023. Epidemiological and microbiological characteristics, as well as patient outcomes, were analyzed and compared across these periods. Results A total of 1,044 patients diagnosed with IE were included. The median (Q1-Q3) age was 57 (44–68) years, with an increasing pattern (p < 0.001). Throughout the study period, the prevalence of intracardiac devices increased, whereas the prevalence of degenerative and congenital heart diseases declined. Among all patients, the most frequently identified pathogens were staphylococci (36.4%), followed by streptococci (14.0%) and enterococci (11.9%). Throughout the three periods, there was a significant increase in staphylococci, with S. aureus emerging as the predominant pathogen in all type IE. The in-hospital mortality rate among all patients was 22.5%. Independent risk factors for in-hospital mortality included ≥ 65 age(OR = 1.9), chronic kidney disease (OR = 1.9), nosocomial acquisition (OR = 2.1), Candida spp. infection (OR = 2.9), prosthetic valve IE (OR = 1.9), vegetation size > 15 mm (OR = 1.6), and central nervous system emboli (OR = 2). Conclusion The epidemiology of IE is undergoing significant changes, leading to shifts in microbiological profiles and clinical presentations. Effective management of IE should be guided by established clinical guidelines while integrating up-to-date epidemiological data to ensure comprehensive and evidence-based patient care.

Introduction Chemosensory food signals are carried by the vagus nerve (VN) from the gut to the brain and these signals contribute to communicating fullness and caloric value of the consumed food in regulatory and reward‐related contexts. Here, we aimed to explore whether neural responses to flavor can be modulated through noninvasive VN stimulation, which can be done transcutaneously (transcutaneous vagus nerve stimulation [tVNS]) on the outer ear via the auricular branch of VN. The ideal stimulation location on the outer ear for tVNS is not agreed on but two candidate locations are cymba conchae and tragus. Methods In this study, we explore the optimal stimulation location for tVNS (cymba conchae, tragus, and cymba conchae and tragus) and timing of tVNS relative to chocolate milk presentation (during, after) in a within‐participants design (15 participants). We examined various measures of efficacy; event‐related potential from electroencephalogram, eye‐blink rate, perceptual and hedonic aspects of flavor, swallowing behavior, and consumption behavior. Results We observed no effect of stimulation location on any of the dependent variables. Unexpectedly, we observed a large effect of food consumption on spontaneous eye‐blink rate. Conclusion In conclusion, overall we did not observe a clear optimal ear location for tVNS‐induced modulation of neurophysiological, perceptual, and behavioral variables. Future studies may confirm whether spontaneous eye‐blink rate can be a sensitive proxy for food reward‐related phasic dopamine shifts.

Background Cyclophosphamide (CYC) is an inactive alkylating agent that transforms the alkyl radicals into other molecules and is used in combination with systemic corticosteroids in the treatment of many childhood rheumatic diseases, such as systemic lupus erythematosus (SLE), and ANCA-associated vasculitis (AAV). In recent years, rituximab (RTX), a B-cell-targeting anti-CD20 monoclonal antibody, has emerged as a new alternative treatment modality over CYC for induction therapy of childhood-onset rheumatic diseases. Clinicians adopt different practices for using CYC particularly in relation to indications, posology, pre-treatment laboratory work-up, post-treatment follow-up, and screening pre- and post-treatment vaccination status. This study aimed to evaluate the principles and approaches of administering CYC therapy in pediatric rheumatology and pediatric nephrology practices and to compare the clinician preferences for CYC and RTX in induction therapy of childhood-onset rheumatic diseases. Methods This study includes a web-based questionnaire executed on 87 participants (56 pediatric rheumatologists (PRs) and 31 pediatric nephrologists (PNs)). Both pediatric subspecialties evaluated and compared the most common indications for CYC treatment, pre-treatment consent protocols, pre-and post-treatment laboratory tests, dosing strategies, and side effects. Results Childhood-onset SLE (95%) and AAV (69%) were the most common diseases for which CYC treatment is used. All clinicians, except 2 PNs prescribed CYC via intravenous route. 61% of the PRs and 71% of PNs reported using a monthly dose of 500 mg/m² CYC for 6 months in accordance with the National Institutes of Health (NIH) protocol. All clinicians conducted pre-CYC treatment assessments of complete blood count and kidney function tests. Hepatitis B (82%), chickenpox (76%), and mumps-measles-rubella (72%) were the most frequently assessed vaccines. Adverse effects associated with CYC include cytopenia (86%), nausea (52%), liver toxicity (20%), hair loss (31%), hemorrhagic cystitis (37%), allergic reactions (16%), dyspnea (5%), and infertility (2%). 9 clinicians stated that they performed gonad-sparing interventions before CYC, which clarifies why CYC was more commonly preferred in the induction therapy of SLE and AAV over RTX by both PRs and PNs. Conclusions Clinicians still tend to choose CYC over RTX in induction therapy of SLE and AAV and mostly prefer the high-dose CYC treatment regimen suggested by the NIH.

The aim of the study is to elucidate demographic characteristics, risk factors, clinical presentations, causative agents, and management approaches pertaining to drug-related anaphylaxis in the paediatric population. This study is a multicenter retrospective study that included paediatric patients aged between 1 month and 18 years, who were admitted to the Pediatric Allergy and Immunology outpatient clinics of 11 participating centres with a presumptive diagnosis of drug-induced anaphylaxis, that fulfilled the standardised criteria for anaphylaxis, between January 2017 and December 2022. A total of 293 anaphylactic episodes presented among 265 patients, of which 48.1% (n 141) were female, were included. The median age of patients during the index episode was 107 months (IQR 56.5–161.5). Anaphylaxis occurred most frequently within hospital settings (62.1%, n 182) compared to home environments (34.1%, n 100). The administration were peroral in 40.3% (n 118), parenteral in 59.7% (n 175) of the cases. While antibiotics (56.7%), non-steroidal anti-inflammatory drugs (25.7%), and chemotherapeutics (3.4%) were the most commonly suspected drug groups, the cephalosporin group, and especially ceftriaxone (27.5% [n 80]) were the leading culprits among antibiotics. The anaphylaxis severity was severe in 39.6% (n 116), and moderate in 54.9% (n 161) of episodes. A biphasic reaction occurred in five patients. Only 72% (n 213) of patients were given adrenaline treatment. There were no fatalities. Diagnostic tests (n 64), including skin prick, intradermal, and drug provocation tests, which were performed between 1 and 120 months after the index reaction, yielded positive results in 23.4% (n 15), 17.2% (n 11), and 20.3% (n 13) of cases respectively, giving a total confirmation of 39 patients. Four patients underwent suspected drug desensitisation protocols. There were no fatalities. Conclusions: Antibiotics, particularly ceftriaxone, were the most commonly implicated agents in paediatric drug-induced anaphylaxis. Non-steroidal anti-inflammatory drugs, particularly ibuprofen, constituted the second most frequently implicated drug group. Paediatric patients experiencing drug-related anaphylaxis warrant algorithmic evaluation to ensure accurate diagnosis, prevent recurrence, and identify safe alternative treatments. What is Known: • Antibiotics, particularly ceftriaxone were the most frequently implicated culprit drugs, followed by NSAIDs, with ibuprofen being the most common within this group. What is New: • To the best of our knowledge, this is the largest multicenter paediatric drug-related anaphylaxis study, involving a large number of patients who evaluated by paediatric allergist. • We propose paediatric patients who experience drug induced anaphylaxis should undergo evaluation at specialized centres, to ensure accurate diagnosis, to prevent recurrence and identify safe alternative treatments.

Acetaldehyde (CH3CHO) is of great industrial importance and serves as a key intermediate in various organic transformations. Photocatalytic production of acetaldehyde from CO2 represents a sustainable route compared to conventional oxidation processes. However, current photocatalytic systems often face challenges, including limited product selectivity and dependence on sacrificial reagents. Here, we present a Cd0.6Zn0.4S (CZS) photocatalyst co‐modified with sulfur vacancies and atomically dispersed Cu (Cu/CZS−Vs) for the efficient conversion of CO2 to acetaldehyde. Charge density analysis reveals that sulfur vacancies induce charge accumulation around the adjacent metal atoms, creating active sites that strongly anchor CO2 and H⁺, thereby promoting CO2 conversion while suppressing the competing hydrogen evolution reaction. The atomically dispersed Cu sites facilitate the conversion of key intermediates (i.e., *CHO and *CO) to the crucial C2 intermediate *OCCHO, which can subsequently be converted to acetaldehyde. As a result, this catalyst achieves an acetaldehyde yield of 121.5 μmol g⁻¹ h⁻¹ with a selectivity of ca. 80 % via photocatalytic CO2 conversion in the absence of sacrificial agents, along with a quantum efficiency of ca. 0.53 % at 400 nm, underscoring its potential for practical CO2 conversion applications. These results are expected to pave the way for future developments in green chemical processes.

Background Inherited burden for disease predisposition in diverse populations is an open question. American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, combined with large population variation databases, promise to provide valuable answers. We recently developed a robust ACMG-based automated variant classification tool and categorized the exome sequencing variants of 730,947 individuals from gnomAD. Methods We leveraged the allele frequency information of variants in 3895 Genomics England PanelApp genes and identified 76,677 pathogenic (P) and 295,356 likely-pathogenic (LP) variants, expanding the ClinVar submissions nearly fivefold. Results We found that, on average, an individual is born with 4.31 P or LP variants, of which 1.59 are compatible with a Mendelian condition, 1 in 12 presents with an actionable genotype, and a total of 372 genes are candidates for carrier screening. Furthermore, a genome-first approach revealed that the likelihood of having a genotype compatible with a disease is highest for congenital (1 in 2.24 individuals; 3.37 billion worldwide) followed by nervous (1 in 3.01; 2.39 billion), blood/immune (1 in 3.29; 2.04 billion), musculoskeletal/connective (1 in 3.65; 1.87 billion), skin (1 in 4.46; 1.62 billion), endocrine/metabolic (1 in 4.53; 1.62 billion), circulatory (1 in 7.26; 994 million), eye (1 in 7.62; 961 million), ear (1 in 8.39; 880 million), genitourinary (1 in 10.15; 750 million), neoplasm (1 in 16.01; 410 million), digestive (1 in 18.26; 312 million) and respiratory (1 in 47.72; 155 million) disorders. Conclusions Evidence-based genetic epidemiology demonstrates the potential of personalized medicine for the implementation of early preventive measures and incentivization of lifestyle changes to enhance healthspan and lifespan. From a societal standpoint, this research demonstrates the importance of informing the public to decrease discrimination and social stigmatization associated with inherited diseases, as an overwhelming majority of individuals are expected to carry germ-line risk variants on average.

Acetaldehyde (CH 3 CHO) is of great industrial importance and serves as a key intermediate in various organic transformations. Photocatalytic production of acetaldehyde from CO 2 represents a sustainable route compared to conventional oxidation processes. However, current photocatalytic systems often face challenges, including limited product selectivity and dependence on sacrificial reagents. Here, we present a Cd 0.6 Zn 0.4 S (CZS) photocatalyst co‐modified with sulfur vacancies and atomically dispersed Cu (Cu/CZS−Vs) for the efficient conversion of CO 2 to acetaldehyde. Charge density analysis reveals that sulfur vacancies induce charge accumulation around the adjacent metal atoms, creating active sites that strongly anchor CO 2 and H ⁺ , thereby promoting CO 2 conversion while suppressing the competing hydrogen evolution reaction. The atomically dispersed Cu sites facilitate the conversion of key intermediates (i.e., *CHO and *CO) to the crucial C 2 intermediate *OCCHO, which can subsequently be converted to acetaldehyde. As a result, this catalyst achieves an acetaldehyde yield of 121.5 μmol g ⁻¹ h ⁻¹ with a selectivity of ca. 80 % via photocatalytic CO 2 conversion in the absence of sacrificial agents, along with a quantum efficiency of ca. 0.53 % at 400 nm, underscoring its potential for practical CO 2 conversion applications. These results are expected to pave the way for future developments in green chemical processes.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized as deficiencies in phenylalanine hydroxylase, leading to neurotoxic effects and neurodevelopmental challenges. Sleep, crucial for cognitive and behavioral development, remains underexplored in PKU populations. This study evaluates sleep characteristics and influencing factors in school-aged children with PKU compared to those with hyperphenylalaninemia (HPA) and healthy controls. A total of 101 children aged 5–10 years participated: 37 with PKU, 31 with HPA, and 33 healthy controls. Sleep quality and disturbances were assessed using the Children’s Sleep Habits Questionnaire (CSHQ) and parent-reported data. Additional factors, including phenylalanine levels and sleep hygiene practices, were analyzed. Despite no significant differences in total CSHQ scores across groups, children with PKU exhibited unique patterns, such as being less likely to awaken by himself or herself. Phenylalanine levels showed no significant correlations with overall sleep characteristics, except for an association with reduced sleep anxiety. Distinct sleep hygiene influences emerged in the HPA and control groups, while no such relationships were observed in PKU. This study underscores the complexity of sleep disturbances in PKU, highlighting the need for future research integrating biological, behavioral, and environmental factors. Identifying determinants of sleep problems will aid in developing tailored interventions to enhance the quality of life for patients with PKU. What is known: • Children with PKU, in addition to the risks associated with chronic illness, may be more susceptible to sleep disturbances due to metabolic and neurochemical imbalances. • Prior studies on PKU and sleep have mainly focused on adult populations, with limited data available for school-aged children. What is new: • The sleep characteristics of PKU, HPA, and healthy controls were generally similar, except for awakening by themselves. • Distinct sleep hygiene influences were identified in the HPA and control groups, while no such associations were observed in the PKU group, highlighting the need for a broader perspective to explore alternative biological, behavioral, and environmental factors affecting sleep regulation in PKU.

Analyzing gene expression data from the Cancer Genome Atlas (TCGA) and similar repositories often requires advanced coding skills, creating a barrier for many researchers. To address this challenge, we developed The Cancer Genome Explorer (TCGEx), a user-friendly, web-based platform for conducting sophisticated analyses such as survival modeling, gene set enrichment analysis, unsupervised clustering, and linear regression-based machine learning. TCGEx provides access to preprocessed TCGA data and immune checkpoint inhibition studies while allowing integration of user-uploaded data sets. Using TCGEx, we explore molecular subsets of human melanoma and identify microRNAs associated with intratumoral immunity. These findings are validated with independent clinical trial data on immune checkpoint inhibitors for melanoma and other cancers. In addition, we identify cytokine genes that can be used to predict treatment responses to various immune checkpoint inhibitors prior to treatment. Built on the R/Shiny framework, TCGEx offers customizable features to adapt analyses for diverse research contexts and generate publication-ready visualizations. TCGEx is freely available at https://tcgex.iyte.edu.tr , providing an accessible tool to extract insights from cancer transcriptomics data.

Heart failure (HF) is a complex clinical condition associated with significant morbidity and mortality. Early diagnosis and effective management at the primary care level are essential for improving patient outcomes and reducing the burden on the healthcare systems. The Eurasian Society of HF and the Turkish Association of Family Medicine developed a guideline that underscores the critical role of natriuretic peptides (NPs) in the early detection, diagnosis, and management of HF. NPs, particularly the N-terminal pro-B-type NP, are a reliable biomarker for identifying HF, guiding treatment decisions, and monitoring disease progression. This guideline emphasizes the importance of measuring the levels of these peptides in primary care so as to detect individuals at risk, confirm the diagnosis of HF in symptomatic patients, and evaluate the treatment response. The recommended thresholds for NP levels account for variations arising from factors such as age, gender, and the presence of other health conditions. B-type natriuretic peptides (BNP) levels ≥ 35 pg/ml or N-terminus-proBNP levels ≥ 125 pg/ml are used to confirm the likelihood of HF in symptomatic patients, enabling timely diagnosis and appropriate intervention. Incorporating NP testing into routine clinical practice enables timely referrals and ensures appropriate management at all stages of HF. Beyond diagnosis, the measurement of NPs provides valuable information about treatment effectiveness and prognosis, allowing clinicians to individualize the treatment. By integrating NP testing into primary care, healthcare providers can facilitate early detection, optimize treatment strategies, and improve the quality of life for patients with or at risk of HF. Thus, this guideline highlights the essential role of primary care physicians in addressing the growing challenges of HF through the effective and evidence-based use of NPs.