bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immunoglobulin A isotype of the Arabian camel (Camelus dromedarius) preserves the dualistic structure of unconventional single-domain and canonical heavy chains
Authors: Conca Walter , Saleh Soad M. , Al-Rabiah Rana , Parhar Ranjit Singh , Abd-Elnaeim Mahmoud , Al-Hindas Hussein , Tinson Alexander , Kroell Katharina Birgit , Liedl Klaus Roman , Collison Kate , Kishore Uday , Al-Mohanna Futwan 
Published: December 2023

IntroductionThe evolution of adaptive immunity in Camelidae resulted in the concurrent expression of classic heterotetrameric and unconventional homodimeric heavy chain-only IgG antibodies. Heavy chain-only IgG bears a single variable domain and lacks the constant heavy (CH) γ1 domain required for pairing with the light chain. It has not been reported whether this distinctive feature of IgG is also observed in the IgA isotype. MethodsGene-specific primers were used to generate an IgA heavy chain cDNA library derived from RNA extracted from the dromedary’s third eyelid where isolated lymphoid follicles and plasma cells abound at inductive and effector sites, respectively. ResultsMajority of the cDNA clones revealed hallmarks of heavy chain-only antibodies, i.e. camelid-specific amino acid substitutions in framework region 1 and 2, broad length distribution of complementarity determining region 3, and the absence of the CHα1 domain. In a few clones, however, the cDNA of the canonical IgA heavy chain was amplified which included the CHα1 domain, analogous to CHγ1 domain in IgG1 subclass. Moreover, we noticed a short, proline-rich hinge, and, at the N-terminal end of the CHα3 domain, a unique, camelid-specific pentapeptide of undetermined function, designated as the inter-α region. Immunoblots using rabbit anti-camel IgA antibodies raised against CHα2 and CHα3 domains as well as the inter-α region revealed the expression of a ~52 kDa and a ~60 kDa IgA species, corresponding to unconventional and canonical IgA heavy chain, respectively, in the third eyelid, trachea, small and large intestine. In contrast, the leporine anti-CHα1 antibody detected canonical, but not unconventional IgA heavy chain, in all the examined tissues, milk, and serum, in addition to another hitherto unexplored species of ~45 kDa in milk and serum. Immunohistology using anti-CHα domain antibodies confirmed the expression of both variants of IgA heavy chains in plasma cells in the third eyelid’s lacrimal gland, conjunctiva, tracheal and intestinal mucosa. ConclusionWe found that in the dromedary, the IgA isotype has expanded the immunoglobulin repertoire by co-expressing unconventional and canonical IgA heavy chains, comparable to the IgG class, thus underscoring the crucial role of heavy chain-only antibodies not only in circulation but also at the mucosal frontiers.
Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia
Authors: Ashenafi Senait , Loreti Marco Giulio , Bekele Amsalu , Aseffa Getachew , Amogne Wondwossen , Kassa Endale , Aderaye Getachew , Brighenti Susanna 
Published: December 2023

BackgroundImmune control of Mycobacterium tuberculosis (Mtb) infection is largely influenced by the extensive disease heterogeneity that is typical for tuberculosis (TB). In this study, the peripheral inflammatory immune profile of different sub-groups of pulmonary TB patients was explored based on clinical disease severity, anemia of chronic disease, or the radiological extent of lung disease.MethodsPlasma samples were obtained from n=107 patients with active pulmonary TB at the time of diagnosis and after start of standard chemotherapy. A composite clinical TB symptoms score, blood hemoglobin status and chest X-ray imaging were used to sub-group TB patients into 1.) mild and moderate-severe clinical TB, 2.) anemic and non-anemic TB, or 3.) limited and extensive lung involvement. Plasma levels of biomarkers associated with inflammation pathways were assessed using a Bio-Plex Magpix 37-multiplex assay. In parallel, Th1/Th2 cytokines were quantified with a 27-multiplex in matched plasma and cell culture supernatants from whole blood stimulated with M. tuberculosis-antigens using the QuantiFERON-TB Gold assay.ResultsClinical TB disease severity correlated with low blood hemoglobin levels and anemia but not with radiological findings in this study cohort. Multiplex protein analyses revealed that distinct clusters of inflammation markers and cytokines separated the different TB disease sub-groups with variable efficacy. Several top-ranked markers overlapped, while other markers were unique with regards to their importance to differentiate the TB disease severity groups. A distinct immune response profile defined by elevated levels of BAFF, LIGHT, sTNF-R1 and 2, IP-10, osteopontin, chitinase-3-like protein 1, and IFNα2 and IL-8, were most effective in separating TB patients with different clinical disease severity and were also promising candidates for treatment monitoring. TB patients with mild disease displayed immune polarization towards mixed Th1/Th2 responses, while pro-inflammatory and B cell stimulating cytokines as well as immunomodulatory mediators predominated in moderate-severe TB disease and anemia of TB.ConclusionsOur data demonstrated that clinical disease severity in TB is associated with anemia and distinct inflammatory immune profiles. These results contribute to the understanding of immunopathology in pulmonary TB and define top-ranked inflammatory mediators as biomarkers of disease severity and treatment prognosis.
Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers
Authors: Najjary Shiva , de Koning Willem , Kros Johan M. , Mustafa Dana A. M. 
Published: December 2023

IntroductionThe incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis.MethodsTo that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors.ResultsOur results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings.ConclusionIn conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.
Optimization design of optical windows for deep-sea pressure-resistant structures based on transition materials
Authors: Wei Yucong , Ma Guoliang , Zhang Hailong , Zhang Xiaowei , Quan Xiangqian 
Published: December 2023

IntroductionThe design of high-pressure optical windows is one of the key tasks in deep-sea exploration, as it directly determines the reliability and maximum operating depth of underwater optical equipment.MethodIn this paper, mechanical modeling and finite element analysis methods are employed to study optical windows.Results and discussionResults show that changes in boundary conditions during loading significantly affect the stress distribution of the window. Based on this conclusion, an optimization design method is proposed, which involves the use of transition materials to reduce the impact of base deformation on the window. The study further analyzes the effects of the transition material’s Young’s modulus, Poisson’s ratio, thickness, and friction coefficient on the stress of the optical window. A calculation method for material selection criteria is proposed to select appropriate transition materials, and actual materials are used for verification. Finally, the reliability of the optimization design scheme based on transition materials is confirmed through high-pressure experiments.
Giant cell arteritis: incidence and phenotypic distribution in Western Norway 2013–2020
Authors: Skaug H. K. , Fevang B. T. , Assmus J. , Diamantopoulos A. P. , Myklebust G. , Brekke L. K. 
Published: December 2023

ObjectivesThere is an increasing awareness of the spectrum of phenotypes in giant cell arteritis (GCA). However, there is sparse evidence concerning the phenotypic distribution which may be influenced by both genetic background and the environment. We established a cohort of all GCA-patients in the Bergen Health Area (Western Norway), to describe the phenotypic distribution and whether phenotypes differ with regards to incidence and clinical features.MethodsThis is a retrospective cohort study including all GCA-patients in the Bergen Health Area from 2013–2020. Data were collected by reviewing patient records, and patients considered clinically likely GCA were included if they fulfilled at least one set of classification criteria. Temporal artery biopsy (TAB) and imaging results were used to classify the patients according to phenotype. The phenotype “cranial GCA” was used for patients with a positive TAB or halo sign on temporal artery ultrasound. “Non-cranial GCA” was used for patients with positive findings on FDG-PET/CT, MRI-, or CT angiography, or wall thickening indicative of vasculitis on ultrasound of axillary arteries. Patients with features of both these phenotypes were labeled “mixed.” Patients that could not be classified due to negative or absent examination results were labeled “unclassifiable”.Results257 patients were included. The overall incidence of GCA was 20.7 per 100,000 persons aged 50 years or older. Overall, the cranial phenotype was dominant, although more than half of the patients under 60 years of age had the non-cranial phenotype. The diagnostic delay was twice as long for patients of non-cranial and mixed phenotype compared to those of cranial phenotype. Headache was the most common clinical feature (78% of patients). Characteristic clinic features occurred less frequently in patients of non-cranial phenotype compared to cranial phenotype.ConclusionThe overall incidence for GCA was comparable to earlier reports from this region. The cranial phenotype dominated although the non-cranial phenotype was more common in patients under 60 years of age. The diagnostic delay was longer in patients with the non-cranial versus cranial phenotype, indicating a need for examination of non-cranial arteries when suspecting GCA.
Uncovering a causal connection between the Lachnoclostridium genus in fecal microbiota and non-alcoholic fatty liver disease: a two-sample Mendelian randomization analysis
Authors: Dai Wanhui , Cai Dandong , Zhou Shuai , Li Ang , Xie Jinsong , Zhang Jie 
Published: December 2023

BackgroundPrevious observational studies have indicated that an imbalance in gut microbiota may contribute to non-alcoholic fatty liver disease (NAFLD). However, given the inevitable bias and unmeasured confounders in observational studies, the causal relationship between gut microbiota and NAFLD cannot be deduced. Therefore, we employed a two-sample Mendelian randomization (TSMR) study to assess the causality between gut microbiota and NAFLD.MethodsThe gut microbiota-related genome-wide association study (GWAS) data of 18,340 individuals were collected from the International MiBioGen consortium. The GWAS summary data for NAFLD from the Anstee cohort (1,483 cases and 17,781 controls) and the FinnGen consortium (894 cases and 217,898 controls) were utilized in the discovery and verification phases, respectively. The inverse variance weighted (IVW) method was used as the principal method in our Mendelian randomization (MR) study, with sensitivity analyses using the MR-Egger, weighted median, simple mode, and weighted mode methods. The MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy. Moreover, a fixed-effect meta-analysis was conducted to verify the robustness of the results.ResultsThe gene prediction results showed that at the genus level, four gut microbiota were causally associated with NAFLD in the GWAS conducted by Anstee et al. The relative abundance of Intestinimonas (OR: 0.694, 95%CI: 0.533–0.903, p = 0.006, IVW), Lachnoclostridium (OR: 0.420, 95%CI: 0.245–0.719, p = 0.002, IVW), and Senegalimassilia (OR: 0.596, 95%CI: 0.363–0.978, p = 0.041, IVW) was negatively associated with NAFLD. The relative abundance of Ruminococcus1 (OR: 1.852, 95%CI: 1.179–2.908, p = 0.007, IVW) was positively correlated with NAFLD. Among them, the Lachnoclostridium genus was validated in FinnGen GWAS (OR: 0.53, 95%CI: 0.304–0.928, p = 0.026, IVW). The Lachnoclostridium genus was also significantly associated with NAFLD risk in the meta-analyses (OR: 0.470, 95%CI: 0.319–0.692, p = 0.0001, IVW). No heterogeneity or pleiotropy was observed.ConclusionThis study provided new evidence of the relationship between the Lachnoclostridium genus and NAFLD, suggesting that augmentation of the relative abundance of the Lachnoclostridium genus through the oral administration of probiotics or fecal microbiota transplantation could be an effective way to reduce the risk of NAFLD.
Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis
Authors: Zheng Qingcong , Wang Du , Lin Rongjie , Chen Yuchao , Huang Haoen , Xu Zixing , Zheng Chunfu , Xu Weihong 
Published: December 2023

BackgroundThe causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method.MethodsThe genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran’s Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results.ResultsIn the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685–1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739–1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826–1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849–1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879–1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680–1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486–1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693–1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis.ConclusionAccording to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.
Short-term outcomes of enhanced recovery after surgery protocol in robotic-assisted McKeown esophagectomy for esophageal cancer: a single-center retrospective cohort study
Authors: Xu Xia , Xiong Jiajun , Xu Zhijie , Hu Zhi , Alai Guha , Yu Lulu , Xia Shaofeng , Lin Yidan 
Published: December 2023

BackgroundThis study aimed to evaluate the short-term outcomes of enhanced recovery after surgery (ERAS) protocol in perioperative robotic-assisted McKeown esophagectomy (RAME) among esophageal cancer patients.MethodsFor this retrospective study, all patients who had undergone RAME with esophageal cancer using ERAS protocol and conventional management strategy at the surgery center of our hospital from February 2019 to March 2022 were performed for analysis.ResultsA total of 211 patients were included. Compared to the conventional group, the ERAS group has shorter median operative time [207 (147.5-267.5) vs. 244 (183-305), P&lt;0.001], time to first flatus (P&lt;0.001), time to out-of-bed activity (P=0.045), and time to liquid diet (P&lt;0.001). In addition, the ERAS group has lower postoperative pain scores (3.62 ± 0.87 vs. 4.54 ± 0.91), shorter duration of analgesia pump [2 (1-3) vs. 3 (2.5-5.5)], shorter postoperative hospital stay [(9 (6-47) vs. 11 (6-79)], shorter postoperative hospital stay within neoadjuvant treated patients [8 (7-43) vs. 13 (8-67], shorter postoperative ICU stay [1 (0-7) vs. 2 (0-15)], and less reoperation rate (7.6% vs. 16.8%). Furthermore, the overall complication rate was significantly lower in the ERAS group (26.1%) than in the conventional group (50.4%). Notably, the ERAS group had lower thoracic fluid drainage volume than the conventional group on postoperative 2-7 days (P&lt;0.05).ConclusionsThe application of ERAS protocol in esophageal cancer patients treated with RAME showed advantages of quick postoperative recovery in contrast to the conventional management strategy.
Emerging therapies in the medical management of thyroid eye disease
Authors: Kamboj Alisha , Harrison Andrew R. , Mokhtarzadeh Ali 
Published: December 2023

IntroductionThyroid eye disease (TED) is an immune-mediated disorder associated with a heterogenous array of manifestations that may unfavorably impact vision and quality of life. As understanding of this entity’s complex pathogenesis has evolved, so have therapies with novel molecular targets offering promise for improved patient outcomes.ResultsEmerging immunologic therapies for the management of thyroid eye disease have diverse mechanisms of actions and routes of administration. Different conventional and biological immunosuppressive agents have been studied as mediators of the autoimmune and autoinflammatory pathways in thyroid eye disease. Teprotumumab – an anti-IGF-1R monoclonal antibody that has recently emerged as a first-line therapy for active, moderate-to-severe TED – has demonstrated statistically significant improvements in proptosis, diplopia, clinical activity score, and quality of life compared to placebo. Currently under investigation are several other agents, with varying administration modalities, that aim to inhibit IGF-1R: VRDN-001 (intravenous), VRDN-002 or VRDN-003 (subcutaneous), lonigutamab (subcutaneous), and linsitinib (oral). Tocilizumab, a monoclonal antibody of interleukin 6, has played a role in the management of multiple autoimmune and inflammatory conditions and may offer promise in TED. Another incipient biologic target for TED management is the neonatal Fc receptor, inhibition of which has potential to decrease recycling of immunoglobulin and antibody levels; agents addressing this target including monoclonal antibodies as well as antibody fragments. Finally, hypolipidemic agents may play a role as mediators of TED-associated inflammation.ConclusionAmong the agents under investigation that aim to decrease ocular morbidity associated with TED are agents that IGF-1R, interleukin 6, and the neonatal Fc receptor. The management of TED continues to expand with novel immunologic approaches for disease therapy.
In silico design of novel bioactive molecules to treat breast cancer with chlorogenic acid derivatives: a computational and SAR approach
Authors: Sehrawat Renu , Rathee Priyanka , Rathee Pooja , Khatkar Sarita , Akkol Esra Küpeli , Khatkar Anurag , Sobarzo-Sánchez Eduardo 
Published: December 2023

Introduction: Cancer is a vast group of diseases comprising abnormal cells that multiply and grow uncontrollably, and it is one of the top causes of death globally. Several types of cancers are diagnosed, but the incidence of breast cancer, especially in postmenopausal women, is increasing daily. Chemotherapeutic agents used to treat cancer are generally associated with severe side effects on host cells, which has led to a search for safe and potential alternatives. Therefore, the present research has been conducted to find novel bioactive molecules to treat breast cancer with chlorogenic acid and its derivatives. Chlorogenic acid was selected because of its known activity in the field.Methods: Several chlorogenic acid derivatives were subjected to computational studies such as molecular docking, determination of absorption, distribution, metabolism, and excretion (ADME), druglikeness, toxicity, and prediction of activity spectra for substances (PASS) to develop a potential inhibitor of breast cancer. The Protein Data Bank (PDB) IDs used for docking purposes were 7KCD, 3ERT, 6CHZ, 3HB5, and 1U72.Result: Exhaustive analysis of results has been conducted by considering various parameters, like docking score, binding energy, types of interaction with important amino acid residues in the binding pocket, ADME, and toxicity data of compounds. Among all the selected derivatives, CgE18, CgE11, CgAm13, CgE16, and CgE9 have astonishing interactions, excellent binding energy, and better stability in the active site of targeted proteins. The docking scores of compound CgE18 were −11.63 kcal/mol, −14.15 kcal/mol, and −12.90 kcal/mol against breast cancer PDB IDs 7KCD, 3HB5, and 1U72, respectively. The docking scores of compound CgE11 were −10.77 kcal/mol and −9.11 kcal/mol against breast cancer PDB IDs 3ERT and 6CHZ, respectively, whereas the docking scores of epirubicin hydrochloride were −3.85 kcal/mol, −6.4 kcal/mol, −8.76 kcal/mol, and −10.5 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5. The docking scores of 5-fluorouracil were found to be −5.25 kcal/mol, −3.43 kcal/mol, −3.73 kcal/mol, and −5.29 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5, which indicates the designed compounds have a better docking score than some standard drugs.Conclusion: Taking into account the results of molecular docking, drug likeness analysis, absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation, and PASS, it can be concluded that chlorogenic acid derivatives hold promise as potent inhibitors for the treatment of breast cancer.