bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of IBI110 (anti-LAG-3 antibody) plus sintilimab (anti-PD-1 antibody) in patients with advanced alveolar soft part sarcoma: Results from a phase II study.
Authors: Liu Jiayong , Tan Zhichao , Fan Zhengfu , Bai Chujie , Xue Ruifeng , Li Shu , Gao Tian , Zhang Lu , Wang Xinyu
Published: June 2024

11559

Background: Lymphocyte-activation gene 3 (LAG-3) has emerged as a novel target for immunotherapy (IO). Co-inhibition of LAG-3 and PD-1 may enhance immune checkpoint inhibition with synergistic effects. Herein, we report a phase II study evaluating the safety and efficacy of an anti-LAG-3 antibody (IBI110) plus sintilimab in patients (pts) with advanced alveolar soft part sarcoma (ASPS). Methods: Eligible pts with metastatic or unresectable ASPS were enrolled in two cohorts: cohort A (IO-naïve, defined as no history of previous immune checkpoint inhibitors, including but not limited to anti-PD-1/PD-L1/CTLA-4 antibodies) and cohort B (IO-failed, defined as imaging-confirmed disease progression after treatment with anti-PD-1/PD-L1 antibodies). All pts received IBI110 200 mg plus sintilimab 200 mg intravenously once every three weeks (Q3W). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS), assessed by the investigator per RECIST v1.1, and safety. Secondary endpoints included overall survival (OS) and 6-month PFS rate. Results: As of January 20, 2024, the study enrolled 28 pts (males: 57.1%, median age: 30.5 years, ECOG PS 0: 100%; TNM stage IV: 100%; lung metastasis: 100%), including 20 pts in cohort A and 8 pts in cohort B. The median treatment duration was 11 cycles. There were 15 pts in cohort A and 4 pts in cohort B remaining on treatment as of the cutoff date. Response was evaluable in 27 pts. The best responses were 3 complete responses (CR), 8 partial responses (PR), and 9 stable diseases (SD) in cohort A; 2 PR and 5 SD in cohort B. ORR was 55.0% in cohort A and 28.6% in cohort B. The 6-month PFS rate was 94.7% in cohorts A and 66.7% in cohort B. At a median follow-up of 8.0 months, median PFS was not reached in cohort A and was 14.7 months in cohort B. Median OS was not reached in both cohorts. Treatment-related adverse events (TRAEs) occurred in 27 (96.4%) pts, including grade ≥3 TRAEs in 9 (32.1%) pts. The most frequent TRAEs were hyperuricemia (57.1%), increased blood lactate dehydrogenase (42.9%), and hypertriglyceridemia (42.9%), all of which were grade 1-2. Immune-related adverse events (irAEs) occurred in 27 (96.4%) pts, including grade ≥3 irAEs in 9 (32.1%) pts. Serious TRAE occurred in 2 (7.1%) pts with type 1 diabetes mellitus. TRAE leading to treatment interruption occurred in 1 (3.6%) pt due to type 1 diabetes mellitus. No TRAE led to treatment discontinuation or death. Conclusions: Co-inhibition of LAG-3 and PD-1 showed encouraging efficacy in pts with advanced ASPS. Compared to anti-PD-1 monotherapy, the combination treatment improved ORR in IO-naïve pts and restored IO effectiveness in previously IO-failed pts. The safety profiles were acceptable and manageable in all pts. Clinical trial information: MR-11-22-004975.
Proactive, automated monitoring of uncontrolled symptoms in prostate cancer survivors across the cancer control continuum.
Authors: Muniz Miguel , Childs Daniel S , Ruddy Kathryn Jean , Grzegorczyk Veronica , Pachman Deirdre R. , Morgans Alicia K. , Cobran Ewan Kemar , Griffin Joan M. , Smith Ashley Wilder , Kroenke Kurt , Loprinzi Charles L. , Costello Brian Addis , Orme Jacob , Riaz Irbaz Bin , Sartor A. Oliver , Mitchell Sandra A. , Cheville Andrea L.
Published: June 2024

12079

Background: Many troublesome symptoms experienced by men with prostate cancer are not specific to a particular disease state or treatment modality. As such, these issues' scope is neither fully appreciated nor characterized in the reporting of clinical trial data. A modern accounting of poorly controlled symptoms is needed to better inform survivorship and supportive care efforts. Methods: Data are drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) study, a cluster-randomized stepped wedge trial examining the effectiveness of routine symptom assessment and management on patient-centered outcomes and healthcare utilization (NCT03892967). This is a population-level study supporting patients with cancer, who are cared for in medical oncology clinics across the Midwest United States. The trial utilizes an automated symptom monitoring system with EHR-enabled algorithms for symptom triage and intervention. The current analysis focuses on pre-intervention surveys. The cohort includes E2C2 participants with prostate cancer (as determined by the Mayo Clinic Cancer Registry) receiving curative or palliative-intent therapies, along with prostate cancer survivors who previously completed their treatment. The prevalence of SPPADE symptoms (sleep disturbance, pain, impaired physical function, anxiety, depression, fatigue [low energy]) was assessed using 0 to 10 numerical rating scales (NRS), with scores of 4-6 indicating moderate symptoms and 7-10 indicating severe symptoms. Results: A total of 1,388 men with prostate cancer completed a pre-intervention survey between March 2019 and January 2023. The median age at completion of first survey was 74 years. The cohort includes patients living in diverse settings, including urban (n=718, 52%), micropolitan (n=250, 18%), small town (n=218, 16%), and rural (n=200, 14%) environments. The proportion of patients experiencing moderate-to-severe symptoms (NRS score ≥4) was 47% for fatigue, 40% for impaired physical function, 32% for sleep disturbance, 27% for pain, 22% for anxiety, and 20% for depression/emotional distress. The three domains with the highest prevalence of severe symptoms (NRS score ≥7) were fatigue (17%), impaired physical function (12%), and sleep disturbance (10%). Conclusions: Proactive symptom monitoring identifies a high overall burden of moderate-to-severe symptoms, particularly fatigue and impaired physical function, among prostate cancer patients and survivors. Collaborative care approaches and symptom control trials are needed to mitigate and manage these burdensome symptoms. Clinical trial information: NCT03892967 . [Table: see text]
A decision support intervention for patients with advanced lung cancer amid growing therapeutic complexity: Results of a randomized controlled trial.
Authors: Villalobos Matthias , Unsoeld Laura , Deis Nicole , Siegle Anja , Thomas Michael
Published: June 2024

12103

Background: In the last decade the therapeutic algorithms in lung cancer have changed dramatically because of the continuous approval of new drugs, leading to steadily improving survival. However, recent studies show that the growing complexity has also led to a negative impact on prognostic awareness and patient-physician communication. In a setting of mostly frail patients, this uncertainty jeopardizes goal-concordant care. Consequently, the guideline recommendations of patient-empowerment and shared decision-making are more important than ever, but evidence-based, comprehensively implemented tools are still lacking. Methods: Randomized controlled, open, mono-center trial (n=138) with two arms: A) use of a decision aid incl. clarification of personal values accompanied by a decision-coaching session vs. B) usual care; stratified block randomization according to the characteristic of preferred decision-making at baseline; primary endpoint: clarity of personal values (Value Clarity Subscale of the Decisional Conflict Scale). Secondary outcomes: patients' self-efficacy (DSES), decisional conflict (DCS), perceived preparation for and involvement in decision-making (PDMS and PICS), general health and emotional state (EQ-5D-5L and HADS). In addition to the descriptive evaluation, group comparisons between the two arms were performed (non-parametric comparison: van Elteren test). Results: The evaluation showed high values for decisional conflict in both groups (total mean score arm A 41,25 and arm B 38,65), exposing relevant conflict in 57,6% of patients, highest in the subscale for information (64,4%) and uncertainty (58,9%). PDMS showed that most patients considered the intervention helpful (“prepare for the next visit with your doctor”: 83,8%, “prepare to talk to your doctor about what matters most to you”: 81,6%, “help to know that decision depends on what matters most to you”: 81,6%). The PICS-subscale “patient information” (active information-seeking behavior) showed a statistically significant difference between the two groups (arm A: 2,86 vs arm B: 3,12; p=0,048). All other outcomes showed no significant differences with equally high DCS scores in both arms’ follow-up. Conclusions: Patients with advanced lung cancer show a strikingly high decisional conflict. Despite successfully empowering perceived preparation for decision-making and decreasing information needs in the encounter with the physician, the intervention was not strong enough to improve significantly the decisional conflict. In a setting of constantly changing oncological information and increasing prognostic uncertainty, tailored support that flexibly adapts to individual needs in decision-making is urgently needed. Clinical trial information: DRKS00028023 .
A phase I study to evaluate the safety and tolerability of JCXH-211 (a self-replicating mRNA encoding IL-12) intratumoral injection in patients with malignant solid tumors: Results from the phase Ia dose escalation.
Authors: Le Ngocdiep T.
Published: June 2024

2539

Background: Although interleukin (IL)-12 demonstrated strong preclinical antitumor activity and potent immune-stimulating potentials clinically, systemic administration of IL-12 protein was associated with poor clinical safety profiles. IL-12 functions locally through paracrine and autocrine mechanisms, thus maximizing local concentration of IL-12 in the tumors is important. JCXH-211 is a self-replicating ribonucleic acid (srRNA) encoding human IL-12 encapsulated in lipid nanoparticles. Intratumoral (IT) administration of JCXH-211 is expected to produce the desired spatiotemporal distribution of IL-12 in the cancer lesions. srRNA features enhanced translatability in immunosuppressed tumor microenvironment (TME) than in normal tissues further limiting off-target toxicity. Additionally, the self-replicating nature of JCXH-211 engages multiple immune effector mechanisms and helps inflame TME. We present interim results of the dose escalation part of JCXH-211 IT injection as monotherapy in patients (pts) with malignant solid tumors. Enrollment for the 100 μg cohort is ongoing and updated data will be presented at the meeting. Methods: Pts with advanced solid tumors suitable for IT injection are enrolled. JCXH-211 at 5, 25, 50, and 100 μg are given every 4 weeks (Q4W). Dose Limiting Toxicities (DLT) are monitored for 28 days after 1st dose. Dose escalation follows “3+3” principle. Tumor assessment is performed Q6W using RECIST v1.1. Results: Ten pts with advanced cancers have been enrolled in 5 μg, 25 μg, and 50 μg cohorts: 3 melanoma (MEL), 3 breast cancer (BC), 2 head and neck cancer (HNSC), 1 nasopharyngeal cancer and 1 sarcoma. Nine pts completed DLT observation without DLT; 1 pt withdrew early. No drug-related SAE was reported. Most drug-related AEs were Grade 1/2 and recovered quickly. Only 1 pt in the 25 μg cohort reported 3 Grade 3 AEs possibly related to drug: lymphocytopenia (2 events) and anemia. Seven pts completed at least one post-dose tumor assessment. Three pts experienced shrinkages of the treated lesions by 13.0%, 33.3% and 43.0%, corresponding to BC, HNSC and MEL in the 5 μg, 25 μg, and 50 μg cohorts, respectively. Tumor shrinkage of 31% was also observed in a non-injected lesion of an HNSC pt receiving 25μg JCXH-211 suggesting abscopal effects. Histopathological analysis of the treated lesions demonstrated increased T and NK cell infiltration (as high as 138 folds) post study drug administration. Conclusions: JCXH-211 IT administration with doses of 5μg, 25μg, 50μg Q4W demonstrated good safety profile. Antitumor activities were observed in the heavily pretreated late-stage pts. Significant increases of T and NK cell infiltration were observed. These data support continued evaluation of JCXH-211 IT. Clinical trial information: NCT05727839 .
Anti-PD-1/TGF-βRII bispecific antibody fusion protein LBL-015 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose-escalation study.
Authors: Li Qun , Zhao Wei , Wang Wei , Chen Po , Niu Zuoxing , Ni Shuqin , Luo Suxia , Qiao Junjing , Wang Mingxi , Li Yong , He Yan , Liu Tao , Li Tao , Cai Shengli , Li Jin
Published: June 2024

2592

Background: LBL-015 is a bispecific fusion protein which consists of fully anti PD-1 monoclonal antibody and TGF-βRII ectodomain, designed to block PD-1/PD-L1 and TGFβ signal pathway, reversing immune suppression and promoting anti-tumor immunity. Here we report the preliminary safety and efficacy of LBL-015 in patients with advanced solid tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-015 in patients with advanced solid tumors that progressed after standard therapy. The dose escalation phase consists of 6 dose cohorts of LBL-015 at 0.3, 1.2, 4, 6, 10, and 20 mg/kg (iv Q2W), using an accelerated titration design (first dose) followed by a 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of December 05, 2023, 25 patients [Demography: 11 (44%) male, median age 59 years (range:24, 72), 23 (92%) ECOG score of 1] received LBL-015 treatment. Tumor types included 7 (28%) colorectal cancer, 6 (24%) renal carcinoma (RCC), 2 (8%) gastric carcinoma, 2 (8%) nasopharyngeal carcinoma and 8 (32%) other tumors. 15 (60%) previously received anti-PD(L)-1 treatment. During the study, 2 DLTs (respiratory failure at grade 5 and pulmonary infection at grade 3, respectively) were observed at the dose of 10 and 20 mg/kg, and the MTD was not reached. 25 patients (100%) experienced TEAEs of any grade and 11 patients (44%) at grade ≥3. The most common grade TEAEs (≥20%) were grade 1-2 and included anaemia, AST increased, γ–GT increased, gingival bleeding, pyrexia, LDH increased, proteinuria, ALT increased, weight decreased, asthenia, bilirubin conjugated increased, decreased appetite, hypoalbuminaemia, asthenia. Treatment interruption and permanent discontinuation of LBL-015 due to TEAEs occurred in 3 (12%) and 2 (8%) patients, respectively. Six patients (24%) experienced SAEs. Out of the 20 patients who underwent at least one efficacy evaluation per RECIST, 1 patient with RCC achieved PR at first image assessment which remained partial response for more than 28 weeks, and 4 patients achieved SD. The ORR and DCR were 5%, and 25%, respectively. Conclusions: LBL-015 has demonstrated good safety profiles in patients with advanced solid tumors. The encouraging preliminary efficacy signals indicated additional studies with a focus on TGFβ signaling pathway deregulated or activated tumors such as RCC, pancreatic cancer, etc. should be further explored. Clinical trial information: NCT05107011 .
Complexity in the timing of the first postnatal ecdysis in snakes
Authors: Lillywhite Harvey B. , Jacobson Elliott R. , Sheehy III Coleman M.
Published: June 2024

Lepidosaurian reptiles, particularly snakes, periodically shed the outer epidermal layers of their skin (ecdysis) to restore or enhance vital functions such as regulating water and gaseous exchange, growth, and protection against insult, infection or physical injury. Although many studies have focused on the nature and mechanisms of skin shedding, little attention has been paid to the timing of the first ecdysis in neonates following birth or hatching. A recent study investigated patterns of the time to first postnatal ecdysis in snakes based on a large dataset taken from the literature. The analysis demonstrated patterns in the time to first postnatal ecdysis related to phylogeny as well as several life history traits. While this assessment provides important advances in our knowledge of this topic, data on known biophysical drivers of ecdysis – temperature and humidity – were largely unavailable and were not evaluated. The first postnatal ecdysis of neonatal snakes can be viewed as an adaptive adjustment to the transition from the aqueous environment of the embryo to the aerial environment of the newborn. Hence, the timing of the first postnatal ecdysis is logically influenced by the aerial environment into which a newborn snake or hatchling finds itself. Therefore, in this Commentary, we first emphasize the putative plasticity of ecdysis with respect to epidermal lipids that structure the water permeability barrier and are established or renewed during ecdysis to reduce transepidermal evaporative water loss. We then discuss the likely importance of biophysical variables as influential covariates that need future investigation as potential co-determinants of the timing of first postnatal ecdysis.
Διερεύνηση της εξελικτικής δύναμης του τουρισμού ευεξίας στο πλαίσιο ενδυνάμωσης της ενδογενούς περιφερειακής ανάπτυξης
Authors: Οικονόμου Γεώργιος
Published: June 2024

Ο τουρισμός ευεξίας αποτελεί ένα σημαντικό τμήμα στην αγορά στο οποίο οι τόποι προορισμού μπορούν να επενδύσουν για να αυξήσουν τις τουριστικές ροές και να αναζωογονήσουν περιοχές δεκτικές σε περεταίρω ανάπτυξη. Η παρούσα εργασία διερευνά τις προτιμήσεις των επισκεπτών για προϊόντα τουρισμού ευεξίας για την ανάπτυξη σχετικών τόπων προορισμού. Η έρευνα περιελάμβανε 595 άτομα και διενεργήθηκε στην περιοχή της Κεντρικής Ελλάδα με τη μέθοδο της προσωπικής συνέντευξης στο πεδίο της έρευνας. Η ανάλυση των δεδομένων πραγματοποιήθηκε σε τρία στάδια. Αρχικά, εφαρμόστηκε η Ανάλυση Σύζευξης για τον καθορισμό εκείνων των συνδυασμών του προτεινόμενου προϊόντος τουρισμού ευεξίας που μεγιστοποιεί την προτίμηση των επισκεπτών. Στο δεύτερο στάδιο, υπολογίστηκε η προθυμία πληρωμής για βελτιώσεις στα χαρακτηριστικά του προϊόντος τουρισμού ευεξίας χρησιμοποιώντας τη Μέθοδο της Υποθετικής Αξιολόγησης. Στο τρίτο στάδιο, χρησιμοποιήθηκε η Θεωρία της Σχεδιαζόμενης Συμπεριφοράς (ΘΣΣ) για τη διερεύνηση της πρόθεσης των δυνητικών επισκεπτών να χρησιμοποιήσουν υπηρεσίες τουρισμού ευεξίας. Τα αποτελέσματα έδειξαν ότι ο συνδυασμός που μεγιστοποιεί την προτίμηση των επισκεπτών είναι η επίσκεψη κατά τους μήνες Σεπτεμβρίου και Οκτωβρίου, με διάρκεια διαμονής 7 ημέρες, με κύριο σκοπό επίσκεψης τον τουρισμό ευεξίας, προτιμώντας υπηρεσίες τουρισμού ευεξίας τόσο για τη σωματική άσκηση όσο και για τη ψυχική/πνευματική ανάτασή τους. Με τη χρήση της λογιστικής παλινδρόμησης η μέση προθυμία πληρωμής υπολογίστηκε στα 47,33 € ανά άτομο ανά ημέρα επίσκεψης. Σε σχέση με τη ΘΣΣ, τα αποτελέσματα επιβεβαίωσαν τις υπό διερεύνηση υποθέσεις, δηλαδή η ‘Στάση’, τα ‘Υποκειμενικά Πρότυπα’ και ο ‘Αντιλαμβανόμενος Έλεγχος απέναντι στη Συμπεριφορά’ επιδρούν σημαντικά και θετικά στην ‘Πρόθεση’ για χρήση υπηρεσιών τουρισμού ευεξίας. Τα εμπειρικά αποτελέσματα έδειξαν ότι η βιωσιμότητα, η ποιότητα και η επιχειρηματικότητα επιδρούν θετικά στην προθυμία πληρωμής. Αντίθετα, η διάρκεια διαμονής στην περιοχή και η ηλικία επιδρούν αρνητικά στην προθυμία πληρωμής. Τα ερευνητικά αποτελέσματα δείχνουν ότι η δόμηση πελατοκεντρικών τουριστικών προϊόντων ενδυναμώνειτις προσπάθειες του προορισμού να αυξήσει την επισκεψιμότητα και να εξελίξει τη σχετική οικονομία. Επιπρόσθετα, η αποτελεσματικότητα στη διαχείριση του τόπου προορισμού μπορείνα ενισχυθεί από τα ερευνητικά αποτελέσματα μέσα από στοχευμένα διαχειριστικά σχέδια.
Microplastics in surface water of different beaches in Chattogram coastal area of Bay of Bengal in Bangladesh
Authors: Das Rimu , Pandit Debasish , Alam Md. Wahidul , Aziz Md. Shah , Bir Joyanta , Hassan Md Mehedi , Uddin Mohammad Rokan , Rahman Md. Habibur , Zereen Ismot
Published: June 2024

Microplastic (MP) pollution in aquatic systems poses a great threat, as these tiny particles contaminate water, harm marine life, and may eventually enter the food chain, endangering ecosystems and human health. The purpose of this study was to assess the presence of MPs in surface-level water samples taken from Chattogram Coastal Area of the Bay of Bengal in Bangladesh. A total of 20 water samples were collected from four sea beaches, spanning the period from September to December 2023. A total of 452 MPs were enumerated from the collected water samples, with 29% observed in Kattoli Beach, 26% in Patenga Beach, 24% in Anowara Beach, and 21% in Banshkhali Beach. MPs ranging from 1-5mm in size were identified as the most prevalent in the study areas. Anowara Beach exhibited a dominant composition of fibers (53%), Banshkhali Beach was characterized by particles (55%), and Patenga Beach and Kattoli Beach displayed a high abundance of fragments (65% and 56%, respectively). The abundance of MPs at Kattoli Beach was significantly high (p<0.05) compared to other beaches. The pollution load index ranged from 1.25-1.49 with the highest index values at Kattoli Beach. The results from this study could be applied as a guide to efficient environmental management for the long-term health of the beaches by reducing the degree of MP load from the coastal and marine ecosystems of Bangladesh.
O frazeologicznym słowniku gwarowym w ujęciu semantycznym (raz jeszcze)
Authors: Przymuszała Lidia
Published: June 2024

The article refers to the previous texts (inter alia Anna Tyrpa, Maciej Rak, Lidia Przymuszała) regarding the postulates of developing a phraseological dictionary of Polish dialects, focusing on the issues of methods of describing dialectal phrasematical material (in alphabetical, semantic and onomasiological order). The aim of this article is indicating the differences in the understanding of what a semantic dictionary and an onomasiological / thematic dictionary are; discussion of methodological problems related to the development of a lexicon from a semantic perspective, as well as an attempt to present (using selected examples) possible methodological solutions.
Przekleństwa z komponentem ‘diabeł’ oraz ich warianty leksykalne w gwarze cieszyńskiej
Authors: Buława Monika
Published: June 2024

Cieszyn curses with the component ‘diabeł’ (represented by the lexemes: diabeł, dziabeł, dias, dzias, diasek, dziasek, czert, kaduk, grzech, czechman) were presented in this article in two main groups: 1) curses such as: niech kogoś diabeł weźmie [may someone be taken by the devil] (e. g. niechby kogoś czechman porwoł); 2) curses such as idź do diabła [go to the devil] (e. g. cióng do diabła), taking into account also elliptical versions. According to this scheme, their lexical variants were also presented (in the broad sense of variance of phraseological units which accepts non-synonymity of replaceable lexical components) with such replaceable elements as, e. g. szargan, drak, ćmok, macek, świński huk (e. g. niech kogoś drak weźmie, do draka) [may someone be taken by the devil; to the devil]. Such idioms were described with special emphasis on specific elements – in the lexical and/or phraseological aspects – for the Cieszyn dialect. What was also analysed was the function played by phraseological variants of curses with the ‘devil’ component (the function is, first of all, related to linguistic taboo).
Alabanda Teritoryumundan Akçaova-Gezirler Basamaklı Kaya Anıtı
Authors: DAĞDEVİREN Memduh , DURNAGÖLÜ Nihal
Published: June 2024

Çalışmanın konusunu, İç Karia Bölgesi kenti olan Alabanda teritoriyumunda bulunan Akçaova-Gezirler Garmahat Harım mevkisinde yeni keşfedilen anıt şeklinde yapılmış basamaklı kaya sunağı oluşturmaktadır. Roma İmparatorluk Dönemi içerisinde değerlendirilen sunak, özellikle yekpare gnays kaya kütlesinin tıraşlanması ile oluşturulan basamak düzenlemesi ile Phryg kökenli basamaklı sunaklarla benzerlik sunmaktadır. Ancak üslup bakımından idollü Phryg örneklerinden ziyade daha yakın konumdaki Karia Bölgesi örnekleriyle benzeşmektedir. Mimari görüntüsüne göre açık hava kült kompleksinin bir parçası durumundaki bağımsız duran basamaklı kaya sunağı, dağlık bir arazide zeytin ve çam ağaçlarının arasında konumlandırılmıştır. Yapısal farklılığı nedeniyle söz konusu sunak tipolojik olarak da literatürdeki diğer örneklerden ayrılmakta ve ayrı bir tipi işaret etmektedir. Bölgede çeşitli arkeolojik araştırmalar yapılmış ancak yoğun bitki örtüsü altında olan kült alanı bugüne kadar keşfedilmemiştir. Bu çalışmayla bugüne kadar keşfedilmemiş olan Kybele ya da onunla özdeşleştirilen bir tanrıçaya hizmet ettiği düşünülen basamaklı kaya sunağının mevcut literatüre kazandırılması ve mevcut tipoloji içindeki yerini alması hedeflenmiştir.
Phonation types and morpho-phonological structure as linguistic prerequisites of tonogenesis
Authors: Zhu Xiaonong
Published: June 2024

ABSTRACT: This paper provides a systematic account of tonogenesis. The emergence of tone is a process of pitch upgrading from an accompanying feature of phonation types to a distinctive feature. It involves three linguistic processes: Various phonation types, clear, breathy, falsetto, etc., which intrinsically induce pitch differences; sonorous mono-syllabic morpheme structure that enhances the pitch differences; and phonologization, which conceptualizes the enhanced pitch differences to a phonological category, tone. A flowchart is designed to show how the preconditions lead to different phono-morphological types of the world’s languages and finally output tone, and its later development. Furthermore, the geographic distributions and ecological constraints of non-modal voices and tone are explored. 摘要: 本文提供一个声调发生的系统解释。声调的产生是一个音高从发声态 的伴随特征提升为区别特征的过程，其间涉及三个步骤：各种发声态 如清洌声、气声、假声等，天然引发音高区别；高响度的单音节语素 结构强化这一音高区别；然后是音法化，即将此强化了的音高区别概 念化为一个音法范畴：声调。本文设计了一个流程图，显示这些前提 条件是如何把世界语言引向不同的音法形态结构并最后产出声调，及 其后续变化。本文还探讨了特殊发声态和声调的地理分布和生态条件。
Shì as a complementizer
Authors: Yang Zhaole
Published: June 2024

ABSTRACT: In this article, it is argued that a purely functional and semantically bleached shì in Mandarin could in many contexts be best analyzed as a complementizer. As such, it is comparable to English that and functions as an (optional) introducer of the clausal arguments. Our survey shows that the morpheme shì as a complementizer occurs after quite a number of clause introducing operators, for instance, epistemic modals, clausal adverbs, clausal conjunctions, and verbs taking clausal objects like psych verbs and speech-act verbs. Like in some other languages, e.g., the West African language Twi and Dutch, the complementizer can merge with a preceding element and the two elements are turned into one frozen combination involving reanalysis and constituency rebracketing. We argue that Mandarin shì has gone through similar developments as complementizer in many frozen combinations such as shuōshì. As a piece of additional evidence, we find that in Gangou dialect, a Mandarin variant, shì can also take on a complementizer function. In the end, based on the fact that shì is used as a demonstrative pronoun in Pre-Qin times, we argue that Mandarin indeed has complementizers from two different sources out of the five major sources across languages listed by Chappell (2017), i.e., shuō , the complementizer (as argued by many) originally from a verb of saying, and shì , originally a demonstrative. 摘要: 本文提出在汉语普通话中，失去其基本语义而仅具有语法功能的“是” 在多种句子类型中均可被分析为小句标句词(complementizer)，用以标记和引导小句论元。通过考察我们发现标句词“是”广泛出现在各种可接引句子的成分之后，比如，知识情态动词，小句层面副词，连结句子的连词以及一些带小句宾语的动词，比如心理类动词和言说类动词。正如西非语言 Twi 和荷兰语，汉语普通话标句词“是”可以通过进一步语法化而失去其独立性，并和其前置成分融合成一种“凝固组合”，比如“说是”。作为旁证，我们也可以在一些汉语方言比如甘沟话中，发现作为标句词使用的“是”。基于“是”在先秦汉语中作为指示词使用，加之“说”在之前文献中被分析为汉语标句词，我们得出结论：汉语小句标句词的来源占 Chappell(2017)归纳的五大类来源中的两类，即言说向标句词“说”和指示向标句词“是”。
Time-domain vector ptychography
Authors: Schweizer T. , Frey H. M. , Rohwer E. , Feurer T.
Published: June 2024

We demonstrate the reconstruction of the instantaneous polarization state of ultrafast laser pulses through vectorial time-domain ptychography. We introduce the formalism, investigate the algorithm’s capacities through simulations, and finally validate it by reconstructing several polarization states from experiments.
Propagation dynamics of orbital angular momentum beams under the hazy scattering environment
Authors: Fu Qin , Zhou Liyu , Huang Xianwei , Bai Yanfeng , Fu Xiquan
Published: June 2024

The disturbance of the scattering medium, such as hazy, can affect the propagation of vortex beams and induce cross−talk within the orbital angular momentum (OAM) spectrum in optical communications based on vortex beams. This paper first validates the integrated scattering phase screen model through experimental beam phase measurements using a simple interferometer. Then, the influence of macroscopic physical parameters of the scattering medium on the OAM spectrum is investigated based on the hazy scattering phase model. It is demonstrated that the larger particle radius, concentration, and thickness will result in a greater cross−talk of the OAM spectrum. Moreover, the behavior of multiplexed vortex beams influenced by the hazy environment is also studied. The results may be a powerful tool to estimate the effect of the scattering medium on beam quality in optical communication based on vortex beams.
Electro-absorption modulated 53 Gbps widely tunable laser based on half-wave V-coupled cavities
Authors: Wang Zhongwen , Meng Jianjun , Chen Qi , Li Qiaoli , Zhu Junqiang , Zhao Jiasheng , He Jian-Jun
Published: June 2024

In this paper, a 53 Gbps widely tunable transmitter is experimentally demonstrated for the first time, to our knowledge. An InGaAlAs/InP multiple-quantum-well (MQW) wafer is used with an identical layer structure for both the V-coupled cavity laser (VCL) and the electro-absorption modulator (EAM). The VCL uses a shallow-etched waveguide to reduce loss, while the EAM uses a deep-etched waveguide to increase the 3-dB modulation bandwidth. With the temperature varying from 19.5 to 30°C, the transmitter achieves wavelength tuning of 42 channels with a spacing of 100 GHz, corresponding to a tuning range of 32.6 nm from 1538.94 to 1571.54 nm. The static extinction ratio (ER) for all channels is higher than 14 dB. The measured 3-dB electro-optic (E0) bandwidth of the transmitter is over 40 GHz, which fits well with the calculated 3-dB bandwidth. At a fixed peak-to-peak driving voltage of 2.4 V, all channels exhibit clearly an open eye diagram with a 53 Gbps non-return-to-zero (NRZ) signal, while the dynamic ER is higher than 4.5 dB.
Low-loss and high-index contrast ultraviolet-C free-standing waveguides made of thermal silicon oxide
Authors: Su Chenming , Jaramillo Concha Claudio A. , Lin Chupao , Quack Niels , Galland Christophe , Le Thomas Nicolas
Published: June 2024

Photonics in the ultraviolet provides an avenue for key advances in biosensing, pharmaceutical research, and environmental sensing. However, despite recent progress in photonic integration, a technological solution to fabricate photonic integrated circuits (PICs) operating in the UV-C wavelength range, namely, between 200 and 280 nm, remains elusive. Filling this gap will open opportunities for new applications, particularly in healthcare. A major challenge has been to identify materials with low optical absorption loss in this wavelength range that are at the same time compatible with waveguide design and large-scale fabrication. In this work, we unveil that thermal silicon oxide (TOX) on a silicon substrate is a potential candidate for integrated photonics in the UV-C, by removing the silicon substrate under selected regions to form single-side suspended ridge waveguides. We provide design guidelines for low-loss waveguide geometries, avoiding wrinkling due to residual intrinsic stress, and experimentally demonstrate waveguides that exhibit optical propagation losses below 3 and 4 dB/cm at a wavelength of 266 nm with claddings of air and water, respectively. This result paves the way for on-chip UV-C biological sensing and imaging.
Spin-vertical-cavity surface-emitting lasers with by-design-defined birefringence for high-speed modulation
Authors: Panajotov K.
Published: June 2024

We propose a new, to the best of our knowledge, type of spin-vertical-cavity surface-emitting laser (VCSEL) with controlled by design birefringence. To this aim, we utilize the so-called columnar thin films (CTFs) in the VCSEL dielectric distributed Bragg mirror and/or in a second dielectric cavity. We design such CTF-VCSELs with pre-defined birefringence and calculate their polarization-resolved resonant longitudinal modes and the corresponding quantum-well confinement factors and threshold gains. Using the spin-flip VCSEL model, we show that such spin CTF-VCSELs can achieve small-signal modulation response with a 3 dB cutoff frequency of several hundreds of GHz.
Design of an aperiodic Cr/C reflective multilayer quarter-wave plate at the carbon K-edge
Authors: Peng You , Li Bin
Published: June 2024

An aperiodic Cr/C reflective multilayer quarter-wave plate is designed and optimized at the carbon K-edge, by implementing both the genetic algorithm (GA) and the non-dominated sorting genetic algorithm II (NSGA-II). The performance is demonstrated using test free electron laser (FEL) pulses simulated by GENESIS to convert the imperfect linearly polarized light to circular polarization; the characteristics are verified by a numerical analysis of the Stokes parameter of the FEL pulses before and after penetration through the multilayer.
Co-transcriptional splicing facilitates transcription of gigantic genes
Authors: Fingerhut Jaclyn M. , Lannes Romain , Whitfield Troy W. , Thiru Prathapan , Yamashita Yukiko M.
Published: June 2024

Although introns are typically tens to thousands of nucleotides, there are notable exceptions. In flies as well as humans, a small number of genes contain introns that are more than 1000 times larger than typical introns, exceeding hundreds of kilobases (kb) to megabases (Mb). It remains unknown why gigantic introns exist and how cells overcome the challenges associated with their transcription and RNA processing. The Drosophila Y chromosome contains some of the largest genes identified to date: multiple genes exceed 4Mb, with introns accounting for over 99% of the gene span. Here we demonstrate that co-transcriptional splicing of these gigantic Y-linked genes is important to ensure successful transcription: perturbation of splicing led to the attenuation of transcription, leading to a failure to produce mature mRNA. Cytologically, defective splicing of the Y-linked gigantic genes resulted in disorganization of transcripts within the nucleus suggestive of entanglement of transcripts, likely resulting from unspliced long RNAs. We propose that co-transcriptional splicing maintains the length of nascent transcripts of gigantic genes under a critical threshold, preventing their entanglement and ensuring proper gene expression. Our study reveals a novel biological significance of co-transcriptional splicing.
Single-step generation of homozygous knockout/knock-in individuals in an extremotolerant parthenogenetic tardigrade using DIPA-CRISPR
Authors: Kondo Koyuki , Tanaka Akihiro , Kunieda Takekazu
Published: June 2024

Tardigrades are small aquatic invertebrates known for their remarkable tolerance to diverse extreme stresses. To elucidate the in vivo mechanisms underlying this extraordinary resilience, methods for genetically manipulating tardigrades have long been desired. Despite our prior success in somatic cell gene editing by microinjecting Cas9 ribonucleoproteins (RNPs) into the body cavity of tardigrades, the generation of gene-edited individuals remained elusive. In this study, employing an extremotolerant parthenogenetic tardigrade species, Ramazzottius varieornatus, we established conditions that led to the generation of gene-edited tardigrade individuals. Drawing inspiration from the direct parental CRISPR (DIPA-CRISPR) technique employed in several insects, we simply injected a concentrated Cas9 RNP solution into the body cavity of parental females shortly before their initial oviposition. This approach yielded gene-edited G0 progeny. Notably, only a single allele was predominantly detected at the target locus for each G0 individual, indicative of homozygous mutations. By co-injecting single-stranded oligodeoxynucleotides (ssODNs) with Cas9 RNPs, we achieved the generation of homozygously knocked-in G0 progeny, and these edited alleles were inherited by G1/G2 progeny. This is the first example of heritable gene editing in the entire phylum of Tardigrada. This establishment of a straightforward method for generating homozygous knockout/knock-in individuals not only facilitates in vivo analyses of the molecular mechanisms underpinning extreme tolerance, but also opens up avenues for exploring various topics, including Evo-Devo, in tardigrades.
Squeezed from the top: “Social Outburst” (2019) and elite overproduction. A study of the dynamics of Chilean political instability from the approach of Structural Demographic Theory
Authors: Muñoz-Rodríguez Manuel , Ferrero Rosana , Luna Juan Pablo , Lima Mauricio
Published: June 2024

On October 18, 2019, Chile experienced the most important social upheaval since the country regained democracy in the late 1980s. The “Social Outbreak” surprised economic and political elites and seemed paradoxical to the international community who had often praised Chile as a model of successful development. In this paper, we used structural-demographic theory to analyze the interaction between the overproduction of elites and the stagnation in the relative income of the population as the underlying structural cause of Chilean political instability. This theory was able to predict the three most significant instances of political tension in the recent history of Chile: the crisis of the late 1960s that culminated in the coup d’état of 1973, popular mobilizations during the 1980s, and the recent student mobilizations and social upheaval. Our results suggest that, at least during the period 1938–2019, Chilean sociopolitical dynamics is determined by the same structural drivers.
The interaction of disease transmission, mortality, and economic output over the first 2 years of the COVID-19 pandemic
Authors: Morgenstern Christian , Laydon Daniel J. , Whittaker Charles , Mishra Swapnil , Haw David , Bhatt Samir , Ferguson Neil M.
Published: June 2024

Background

The COVID-19 pandemic has caused over 7.02 million deaths as of January 2024 and profoundly affected most countries’ Gross Domestic Product (GDP). Here, we study the interaction of SARS-CoV-2 transmission, mortality, and economic output between January 2020 and December 2022 across 25 European countries.

Methods

We use a Bayesian mixed effects model with auto-regressive terms to estimate the temporal relationships between disease transmission, excess deaths, changes in economic output, transit mobility and non-pharmaceutical interventions (NPIs) across countries.

Results

Disease transmission intensity (logRt) decreases GDP and increases excess deaths, where the latter association is longer-lasting. Changes in GDP as well as prior week transmission intensity are both negatively associated with each other (-0.241, 95% CrI: -0.295 - -0.189). We find evidence of risk-averse behaviour, as changes in transit and prior week transmission intensity are negatively associated (-0.055, 95% CrI: -0.074 to -0.036). Our results highlight a complex cost-benefit trade-off from individual NPIs. For example, banning international travel is associated with both increases in GDP (0.014, 0.002—0.025) and decreases in excess deaths (-0.014, 95% CrI: -0.028 - -0.001). Country-specific random effects, such as the poverty rate, are positively associated with excess deaths while the UN government effectiveness index is negatively associated with excess deaths.

Interpretation

The interplay between transmission intensity, excess deaths, population mobility and economic output is highly complex, and none of these factors can be considered in isolation. Our results reinforce the intuitive idea that significant economic activity arises from diverse person-to-person interactions. Our analysis quantifies and highlights that the impact of disease on a given country is complex and multifaceted. Long-term economic impairments are not fully captured by our model, as well as long-term disease effects (Long COVID).
Extracellular ATP/P2X7 receptor, a regulatory axis of migration in ovarian carcinoma-derived cells
Authors: Nuñez-Ríos José David , Reyna-Jeldes Mauricio , Mata-Martínez Esperanza , Campos-Contreras Anaí del Rocío , Lazcano-Sánchez Iván , González-Gallardo Adriana , Díaz-Muñoz Mauricio , Coddou Claudio , Vázquez-Cuevas Francisco G.
Published: June 2024

ATP is actively maintained at high concentrations in cancerous tissues, where it promotes a malignant phenotype through P2 receptors. In this study, we first evaluated the effect of extracellular ATP depletion with apyrase in SKOV-3, a cell line derived from metastatic ovarian carcinoma. We observed a decrease in cell migration and an increase in transepithelial electrical resistance and cell markers, suggesting a role in maintaining a mesenchymal phenotype. To identify the P2 receptor that mediated the effects of ATP, we compared the transcript levels of some P2 receptors and found that P2RX7 is three-fold higher in SKOV-3 cells than in a healthy cell line, namely HOSE6-3 (from human ovarian surface epithelium). Through bioinformatic analysis, we identified a higher expression of the P2RX7 transcript in metastatic tissues than in primary tumors; thus, P2X7 seems to be a promising effector for the malignant phenotype. Subsequently, we demonstrated the presence and functionality of the P2X7 receptor in SKOV-3 cells and showed through pharmacological approaches that its activity promotes cell migration and contributes to maintaining a mesenchymal phenotype. P2X7 activation using BzATP increased cell migration and abolished E-cadherin expression. On the other hand, a series of P2X7 receptor antagonists (A438079, BBG and OxATP) decreased cell migration. We used a CRISPR-based knock-out system directed to P2RX7. According to the results of our wound-healing assay, SKOV3-P2X7KO cells lacked receptor-mediated calcium mobilization and decreased migration. Altogether, these data let us propose that P2X7 receptor is a regulator for cancer cell migration and thus a potential drug target.
Broccoli aptamer allows quantitative transcription regulation studies in vitro
Authors: van der Sijs Amanda , Visser Thomas , Moerman Pepijn , Folkers Gert , Kegel Willem
Published: June 2024

Quantitative transcription regulation studies in vivo and in vitro often make use of reporter proteins. Here we show that using Broccoli aptamers, quantitative study of transcription in various regulatory scenarios is possible without a translational step. To explore the method we studied several regulatory scenarios that we analyzed using thermodynamic occupancy-based models, and found excellent agreement with previous studies. In the next step we show that non-coding DNA can have a dramatic effect on the level of transcription, similar to the influence of the lac repressor with a strong affinity to operator sites. Finally, we point out the limitations of the method in terms of delay times coupled to the folding of the aptamer. We conclude that the Broccoli aptamer is suitable for quantitative transcription measurements.
Asthma Care from Home: Study protocol for an effectiveness-implementation evaluation of a virtually enabled asthma care initiative in children in rural NSW
Authors: Mackle Ryan , Crespo Gonzalez Carmen , Chan Mei , Hodgins Michael , Hu Nan , Angell Blake , Owens Louisa , Fletcher Jeffery , McCrossin Timothy , Piper Susie , Doyle Aunty Kerrie , Woolfenden Sue , Gould Bronwyn , Ward Flic , Lingam Raghu , Jaffe Adam , Gray Melinda , Homaira Nusrat ,   on behalf of the Asthma Care from Home Collaborative Group
Published: June 2024

Background

Asthma is the leading source of unscheduled hospitalisation in Australian children, with a high burden placed upon children, their parents/families, and the healthcare system. In Australia, there are widening disparities in paediatric asthma care including inequitable access to comprehensive ongoing and planned asthma care for children.

Methods

The Asthma Care from Home Project is a comprehensive virtually enabled asthma model of care that aims to a. supports families, communities and healthcare providers, b. flexible and locally acceptable, and c. allow for adoption of innovations such as digital technologies so that asthma care can be provided “from home”, reduce potentially preventable asthma hospitalisation, and ensure satisfaction at a patient, family, and healthcare provider level. The model of care includes standardisation of discharge care through provision of an asthma discharge resource pack containing individual asthma action plan, follow-up letters for the child’s general practitioner (GP) and school/child care, and access to online asthma educational sessions and resource; post-discharge care coordination through text message reminders for families for regular GP review, email correspondence with their child’s GP and school/childcare; and virtual home visits to discuss home environmental triggers, provide personalised asthma education and respond to parental concerns relating to their child’s asthma. This study is comprised of three components: 1) a quasi-experimental pre/post impact evaluation assessing the impact of the model on healthcare utilisation and asthma control measures; 2) a mixed-methods implementation evaluation to understand how and why our intervention was effective or ineffective in producing systems change; 3) an economic evaluation to assess the cost-effectiveness of the proposed model of care from a family and health services perspective.

Discussion

This study aims to improve access to asthma care for children in rural and remote areas. Implementation evaluation and economic evaluation will provide insights into the sustainability and scalability of the asthma model of care.
The nexus between the attitudes and self-concepts of gifted students in an Arab context
Authors: Opoku Maxwell Peprah , Moustafa Ashraf , Alsheikh Negmeldin , Anwahi Noora , Aljaberi Mariam , Alkhateri Thara , Almeqbaali Aysha , Elhoweris Hala
Published: June 2024

Background

The research literature has reported the need for educators to develop suitable programs geared toward the nurturance of gifted students. Although some non-Western countries have adopted policies to foster the growth of exceptional students, their contributions to research in gifted education are limited. To expand the literature on gifted education, this study was guided by Ajzen’s theory of planned behavior to explore the attitudes and self-conceptions of gifted and talented students in the United Arab Emirates.

Methods

The revised Self-Perception Profile for Children and Opinions About the Gifted and Their Education scales were used to collect data from 150 high school students in Abu Dhabi, one of seven states (emirates) in the United Arab Emirates. AMOS software version 29 was used to conduct confirmatory factor and path analyses. To evaluate the differences between the background variables on attitudes and self-concepts, t-tests were calculated using SPSS software version 28.

Results

The study found a relationship between the attitudes and self-concepts of students regarding their participation in enrichment programs. The hypothesized moderation effect of demographic variables on the relationship between attitudes and self-concepts was not supported.

Conclusion

The study’s limitations and implications for educators in the United Arab Emirates to prioritize programs geared toward developing the attitudes and self-concepts of gifted students are discussed in detail.