bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chloroplast genome sequencing and divergence analysis of 18 Pyrus species: insights into intron length polymorphisms and evolutionary processes
Authors: Kim Jung Sun , Chung Hoyong , Park Bohyeon , Veerappan Karpagam , Kim Yoon-Kyung 
Published: October 2024

Pears constitute an essential temperate crop and are primarily produced through interspecific hybridization owing to self-incompatibility that complicates their breeding history. To address this, we sequenced the complete chloroplast (cp) genomes of 18 Pyrus and one Malus species using the Illumina HiSeq4000 platform. The cp genomes ranged from 159,885 bp to 160,153 bp and exhibited a conserved circular DNA structure with an average GC content of 36.5%. Each cp genome contained 127 genes, including 83 protein-coding, 36 tRNA, and 8 rRNA genes. Divergence analysis with mVISTA showed high conservation in the coding regions and notable variations in the non-coding regions. All species shared 17 intron-containing genes, with ycf3 and clpP each having two introns. Five intron-containing genes (ndhB, rpl2, rps12, trnA-UGC, and trnE-UUC) were located in the inverted repeat regions, while trnL-UAA was located in the large single-copy region, with conserved intron lengths across Pomoideae. We identified polymorphic intron sequences in the rpl22, petB, clpP, ndhA, and rps16 genes and designed primers for these regions. Notably, the two Pyrus ussuriensis accessions Doonggeullebae and Cheongdangrori showed intron-length polymorphisms despite being classified as the same species. Phylogenetic analysis of the cp genome sequences revealed two major clusters, indicating distinct maternal lineages and evolutionary origins. This study underscores the importance of cp gene polymorphisms in P. fauriei, P. calleryana, P. ussuriensis, and P. pyrifolia, providing valuable insights into Pyrus evolution as well as aiding in the conservation and breeding of pear germplasm.
Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach
Authors: de Bruijn Suzanne E. , Panneman Daan M. , Weisschuh Nicole , Cadena Elizabeth L. , Boonen Erica G. M. , Holtes Lara K. , Astuti Galuh D. N. , Cremers Frans P. M. , Leijsten Nico , Corominas Jordi , Gilissen Christian , Skowronska Anna , Woodley Jessica , Beggs Andrew D. , Toulis Vasileios , Chen Di , Cheetham Michael E. , Hardcastle Alison J. , McLaren Terri L. , Lamey Tina M. , Thompson Jennifer A. , Chen Fred K. , de Roach John N. , Urwin Isabella R. , Sullivan Lori S. , Roosing Susanne 
Published: October 2024

IntroductionAutosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow.MethodsGenetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using a smMIPs or genomic qPCR-based approach tailored for the RP17 locus. Suspected copy number changes were validated using high-density SNP-array genotyping, and SV breakpoint characterization was performed by mutation-specific breakpoint PCR, genome sequencing and, if required, optical genome mapping. In silico modeling of novel SVs was performed to predict the formation of neo-TADs and whether ectopic contacts between the retinal enhancers and the GDPD1-promoter could be formed.ResultsUsing this workflow, potential RP17-SVs were detected in eight probands of which seven were confirmed. Two novel SVs were identified that are predicted to cause TAD rearrangement and retinal enhancer-GDPD1 contact, one from Germany (DE-SV9) and three with the same SV from the United States (US-SV10). Previously reported RP17-SVs were also identified in three Australian probands, one with UK-SV2 and two with SA-SV3.DiscussionIn summary, we describe a validated multi-step pipeline for reliable and efficient RP17-SV discovery and expand the range of disease-associated SVs. Based on these data, RP17-SVs can be considered a frequent cause of adRP which warrants the inclusion of RP17-screening as a standard diagnostic test for this disease.
Case report: Adult patient with WWOX developmental and epileptic encephalopathy: 40 years of observation
Authors: Teplyshova Anna , Sharkov Artem 
Published: October 2024

WWOX developmental and epileptic encephalopathy is characterised by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. This report presents for the first time a clinical case of an adult patient with a homozygous likely pathogenic variant (p.Thr12Met) in the WWOX gene, with more than 40 years of follow-up. The patient had refractory epilepsy with various types of seizures during his life: mainly epileptic spasms, autonomic, myoclonic, tonic seizures, and absences. The patient had a prominent developmental delay with a lack of expressive speech, but by the age of 3, he had acquired the skills to sit, crawl, and walk with support. In adolescence, there was an acute regression of acquired skills to a total absence of independent motor activity. The patient had dysmorphic features, such as upslanting palpebral fissures, arched eyebrows, and hypertelorism. For many years, the patient was given a diagnosis of cerebral palsy; 38 years after the onset of the disease, he was given a molecular genetic diagnosis of WWOX-associated developmental and epileptic encephalopathy. Our observation illustrates the natural history of WWOX-DEE and the high clinical significance of early genetic diagnostics for identifying the cause of developmental delay and resistant epilepsy.
Pre-training with a rational approach for antibody sequence representation
Authors: Gao Xiangrui , Cao Changling , He Chenfeng , Lai Lipeng 
Published: October 2024

IntroductionAntibodies represent a specific class of proteins produced by the adaptive immune system in response to pathogens. Mining the information embedded in antibody amino acid sequences can benefit both antibody property prediction and novel therapeutic development. However, antibodies possess unique features that should be incorporated using specifically designed training methods, leaving room for improvement in pre-training models for antibody sequences.MethodsIn this study, we present a Pre-trained model of Antibody sequences trained with a Rational Approach for antibodies (PARA). PARA employs a strategy conforming to antibody sequence patterns and an advanced natural language processing self-encoding model structure. This approach addresses the limitations of existing protein pre-training models, which primarily utilize language models without fully considering the differences between protein sequences and language sequences.ResultsWe demonstrate PARA’s performance on several tasks by comparing it to various published pre-training models of antibodies. The results show that PARA significantly outperforms existing models on these tasks, suggesting that PARA has an advantage in capturing antibody sequence information.DiscussionThe antibody latent representation provided by PARA can substantially facilitate studies in relevant areas. We believe that PARA’s superior performance in capturing antibody sequence information offers significant potential for both antibody property prediction and the development of novel therapeutics. PARA is available at https://github.com/xtalpi-xic.
Prognostic implications of a CD8+ TEMRA to CD4+Treg imbalance in mandibular fracture healing: a prospective analysis of immune profiles
Authors: Voss Jan Oliver , Pivetta Fabio , Elkilany Aboelyazid , Schmidt-Bleek Katharina , Duda Georg N. , Odaka Kento , Dimitriou Ioanna Maria , Ort Melanie Jasmin , Streitz Mathias , Heiland Max , Koerdt Steffen , Reinke Simon , Geissler Sven 
Published: October 2024

IntroductionOpen reduction and fixation are the standard of care for treating mandibular fractures and usually lead to successful healing. However, complications such as delayed healing, non-union, and infection can compromise patient outcomes and increase healthcare costs. The initial inflammatory response, particularly the response involving specific CD8+ T cell subpopulations, is thought to play a critical role in healing long bone fractures. In this study, we investigated the role of these immune cell profiles in patients with impaired healing of mandibular fractures.Materials and methodsIn this prospective study, we included patients with mandibular fractures surgically treated at Charité – Universitätsmedizin Berlin, Germany, between September 2020 and December 2022. We used follow-up imaging and clinical assessment to evaluate bone healing. In addition, we analyzed immune cell profiles using flow cytometry and quantified cytokine levels using electrochemiluminescence-based multiplex immunoassays in preoperative blood samples.ResultsOut of the 55 patients enrolled, 38 met the inclusion criteria (30 men and 8 women; mean age 32.18 years). Radiographic evaluation revealed 31 cases of normal healing and 7 cases of incomplete consolidation, including 1 case of non-union. Patients with impaired healing exhibited increased levels of terminally differentiated effector memory CD8+ T cells (TEMRA) and a higher TEMRA to regulatory T cell (Treg) ratio, compared with those with normal healing.ConclusionsOur analysis of mandibular fracture cases confirms our initial hypothesis derived from long bone fracture healing: monitoring the TEMRA to Treg ratio in preoperative blood can be an early indicator of patients at risk of impaired bone healing. Radiologic follow-up enabled us to detect healing complications that might not be detected by clinical assessment only. This study highlights the potential of individual immune profiles to predict successful healing and may form the basis for future strategies to manage healing complications.
Neutrophil extracellular traps as immunofibrotic mediators in RA-ILD; pilot evaluation of the nintedanib therapy
Authors: Venetsanopoulou Aliki I. , Ntinopoulou Maria , Papagianni Eleni , Koletsos Nikolaos , Voulgari Paraskevi V. , Chrysanthopoulou Akrivi 
Published: October 2024

ObjectiveRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a significant pulmonary complication of RA. This study tried to elucidate the mechanisms enhancing inflammation and causing lung injury in RA-ILD, focusing on the role of neutrophil extracellular traps (NETs). The study also investigated the potential benefits of nintedanib in advanced disease.MethodsNine RA-ILD patients and nine healthy controls were included in the study. Inflammatory markers in patients’ circulation were evaluated with immunoassays. The formation of NETs was examined using a citrullinated histone H3 (CitH3) ELISA and cell immunofluorescence. Inflammatory proteins expressed in neutrophils/NETs were studied with real-time qPCR and NET ELISA. To assess the effect of nintedanib, an intracellular tyrosine kinase inhibitor with antifibrotic properties, in RA-ILD a paired study was conducted in five patients before treatment administration and 16 weeks later.ResultsThe soluble terminal complement complex sC5b-9 and the levels of CitH3 were significantly elevated in patients with RA-ILD, compared to healthy controls. In addition, neutrophils isolated from RA-ILD patients released NETs enriched with tissue factor and interleukin-17A. Inflammatory NETs had a dynamic role, increasing the fibrotic potential of human pulmonary fibroblasts (HPFs). On the other hand, nintedanib treatment decreased NETs and sC5b-9 levels in RA-ILD patients.ConclusionThe findings propose an interplay between circulating NETs and HPFs, establishing the immunofibrotic aspects of RA-ILD. They also support the effectiveness of nintedanib in reducing key pathological processes of the disease. Further research is needed to fully understand these mechanisms and optimize treatment strategies for RA-ILD.
Enhancement of a one-step membrane technique for the treatment of large bone defects by pre-seeding the membrane with CD8 lymphocyte depleted bone marrow mononuclear cells in a rat femoral defect model
Authors: Penna-Martinez Marissa , Kammerer Andreas , Stützle Pia , Fees Sabatian , Behr Savina , Schaible Inna , Schröder Katrin , Verboket René Danilo , Neijhoft Jonas , Marzi Ingo , Nau Christoph , Henrich Dirk 
Published: October 2024

BackgroundThe one-step membrane technique, using a human acellular dermal matrix (hADM), is an experimental method for treating large bone defects. This eliminates the need for the Masquelet membrane induction step, shortening the procedure while maintaining effectiveness. However, previous studies showed that colonizing hADM with bone marrow mononuclear cells (BMC) worsens healing, likely due to the presence of CD8+ lymphocytes, which negatively affect bone regeneration. This study aims to investigate whether the negative impact of BMC on bone healing in this technique is due to the CD8+ cell population.Materials and methodsA 5 mm femoral defect was created in 25 male Sprague-Dawley rats, divided into three groups (G1-G3). BMC were isolated from syngenic donor rats, with CD8+ lymphocytes removed magnetically from the BMC fraction in one group. The defects were filled with bone chips and wrapped with differently treated hADM: G1 received native hADM, G2 received hADM+BMC, and G3 received hADM+BMC-CD8. After 8 weeks, the femurs were evaluated through radiological, biomechanical, and histological examinations.ResultsBone defects and bone mineral density (BMD) were significantly improved in G3 (hADM+BMC-CD8) compared to G2 (hADM+BMC). Bone volume, bone formation, and median bending stiffness were higher in G3. Immunohistological analysis showed a significant decrease in CD8 cell count in G3, with a lower percentage of IFNγ-producing cells compared to G2.ConclusionDepleting CD8+ cells from BMC before colonizing hADM significantly improved bone healing, likely due to changes in the local mediator environment. This suggests that preoperative colonization with CD8+-depleted BMC could enhance the one-step membrane technique.
Comparing PD-L1 with PD-1 antibodies combined with lenvatinib and hepatic arterial infusion chemotherapy for unresectable hepatocellular carcinoma
Authors: Li Shaohua , Mei Jie , Zhao Rongce , Zhou Jing , Wang Qiaoxuan , Lu Lianghe , Li Jibin , Zheng Lie , Wei Wei , Guo Rongping 
Published: October 2024

BackgroundA combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and immune checkpoint inhibitors (ICIs) yields a high tumor response rate and survival benefit in unresectable hepatocellular carcinoma (uHCC). However, the selection criteria for different ICIs remain unclear. This study aims to compare the efficacy and safety of PD-1/PD-L1 antibodies combined with HAIC and lenvatinib.MethodsThis retrospective study included 184 patients with uHCC treated with HAIC+lenvatinib+PD-1/PD-L1 antibody from June 2019 to January 2022. We utilized propensity score matching (PSM) to select and match 60 patients treated with HAIC + durvalumab + lenvatinib (HDL) against 60 patients treated with HAIC + PD-1 antibodies + lenvatinib (HPL) to compare the efficacy and safety profiles of these two groups.ResultsAfter PSM, the baseline characteristics were well-balanced between the HDL and HPL groups. The overall survival (p = 0.293) and progression-free survival (p = 0.146) showed no significant difference. The objective response rate (ORR) was higher in the HDL group compared to the HPL group according to modified RECIST (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040), respectively. The incidence of grade 3 or 4 adverse events (AEs) was 10.0% and 18.3% (p = 0.191) in the HDL and HPL groups, respectively.ConclusionsPD-L1 antibody appears to be a preferable companion in the combination therapy of HAIC + ICIs + lenvatinib compared to PD-1 antibody, showing higher ORR and relatively lower incidence of severe AEs. Further prospective studies involving a larger patient population are warranted.
Perceived quality of maternal care and its barriers based on women’s perspective in hospitals of Northwest Ethiopia: a qualitative study
Authors: Mekie Maru , Belachew Yismaw Yimam , Chanie Ermias Sisay , Bayih Wubet Alebachew , Fenta Setegn Muche , Masresha Gedefew Abeje , Ferede Wassie Yazie , Addisu Dagne 
Published: October 2024

BackgroundThe Sustainable Development Goals (SDGs) in health focus on achieving equity to reduce maternal mortality disparities among subpopulations globally. The goal is to lower the maternal mortality ratio (MMR) to below 70 per 100,000 live births by 2030 for countries with an MMR below 420 in 2010. For those exceeding 420, the target is to keep the MMR below 140 by 2030. This target could not be achieved unless quality maternal health care service is implemented in all health care settings. This study aimed to assess the quality of maternal care and perceived barriers based on women’s perspectives among women who receive delivery services in hospitals of South Gondar Zone, Northwest, Ethiopia.MethodsA phenomenological method was implemented to explore women’s perspectives on quality maternal care and its perceived barriers. An in-depth interview (IDI) was used to collect data using a semi-structured in-depth interview guide. The study was conducted from January 1–30, 2021. All in-depth interview notes were translated into meaningful notes. Then notes were organized by coding texts into meaningful elements using open code version 4.03 software.ResultsThe majority (14 in 20) tried to interpret quality care in terms of respect during procedures, providing family support, and timely care. Some (6 in 20) tried to associate quality care with the competency of care providers, the cleanliness of the procedure, and privacy during care. With regards to perceived barriers to quality care, the majority (15 in 20) of the IDI participants agreed that a high caseload, limited drugs, and administrative problems were barriers to providing quality maternal care.ConclusionParticipants articulate a multifaceted understanding of quality maternal care that encompasses emotional support, accessibility, cleanliness, timely interventions, and respectful treatment. They also identify significant barriers that stem from facility limitations, provider attitudes and knowledge, and administrative inefficiencies. Addressing these barriers is essential for enhancing the quality of maternal health services.
Integrating planetary health education into tertiary curricula: a practical toolbox for implementation
Authors: Lokmic-Tomkins Zerina , Barbour Liza , LeClair Jessica , Luebke Jeneile , McGuinness Sarah L. , Limaye Vijay S. , Pillai Parvathy , Flynn Maxfield , Kamp Michael A. , Leder Karin , Patz Jonathan A. 
Published: October 2024

ObjectiveTo present a series of case studies from our respective countries and disciplines on approaches to implementing the Planetary Health Education Framework in university health professional education programs, and to propose a curriculum implementation and evaluation toolbox for educators to facilitate the adoption of similar initiatives in their programs. We emphasize the importance of applying an Indigenous lens to curriculum needs assessment, development, implementation, and evaluation.MethodsCase studies from Australia and United States were collated using a six-stage design-based educational research framework (Focus, Formulation, Contextualization, Definition, Implementation, Evaluation) for teaching planetary health and methods of curriculum evaluation. These components were then mapped to derive the curriculum implementation toolbox reflecting the six-stage design-based educational research framework.ResultsThe case studies demonstrated different approaches to successful integration of the Planetary Health Education Framework in medicine, nursing, public health, and allied health disciplines. This integration often involved Indigenous perspectives on environmental stewardship, holistic health, and community well-being into the curriculum. The case studies also highlighted the importance of community engagement, cultural competency, and interdisciplinary collaboration in curriculum development. Findings from case studies were used to propose a curriculum implementation toolbox to assist educators in adapting and integrating planetary health education into their own programs.DiscussionWhile valuable frameworks for teaching planetary health in health science programs exist, challenges remain in implementing these frameworks in real-world educational environments. The proposed curriculum implementation toolbox offers practical strategies and resources for educators to incorporate these principles into their teaching. Additionally, the case studies reported here contribute to the growing body of literature on planetary health education pertinent to addressing the triple planetary crisis.
Clinical efficacy of Endostar continuous infusion combined with concurrent chemoradiotherapy in the treatment of oesophageal squamous cell carcinoma
Authors: Du Xinglong , Ji Yuting , Qin Wenqiang , Wei Jie 
Published: October 2024

ObjectiveTo evaluate the effectiveness and safety of concurrent chemoradiotherapy using Endostar continuous infusion for treating oesophageal squamous cell carcinoma (OSCC).MethodA total of 62 patients with oesophageal carcinoma were divided into three groups: the Endostar continuous infusion group (n = 27), the Endostar intravenous drip group (n = 21) and the concurrent chemoradiotherapy group (n = 14). All patients underwent oesophageal radiotherapy (56–60 Gy) alongside concurrent chemotherapy (4 mg of raltitrexed +100 mg of oxaliplatin, two cycles). In the Endostar continuous infusion group, 210 mg of Endostar was administered via infusion once every 3 weeks for 72 h, repeated for two cycles. The Endostar intravenous drip group received a dosage of 15 mg/day of Endostar, administered once daily for 14 days, repeated for two cycles. The objective response rate (ORR) (complete remission + partial remission), progression-free survival (PFS), 2-year overall survival (2y-OS) and adverse reactions were observed.ResultsIn the Endostar continuous infusion, intravenous drip and concurrent chemoradiotherapy groups, the ORR was 100, 95.2 and 78.6%, respectively (p &lt; 0.05). There was a statistically significant difference between the continuous infusion and concurrent chemoradiotherapy groups (p &lt; 0.05). However, there was no statistically significant difference between the continuous infusion and intravenous drip groups or the intravenous drip and concurrent chemoradiotherapy groups (p &gt; 0.05). The continuous infusion and intravenous drip groups had higher PFS rates than the concurrent chemoradiotherapy group (p &lt; 0.05). Regarding the 2y-OS rate, no statistically significant difference was observed among the three groups (p &gt; 0.05). Furthermore, there was no statistically significant difference in adverse reactions among the groups (p &gt; 0.05).ConclusionConcurrent chemotherapy based on endostatin is effective and safe in the treatment of OSCC. Continuous 3-day Endostar infusion treatment can significantly enhance both short-and long-term therapy efficacy in patients while maintaining a high level of safety.