bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of a macrophage carbamylated proteome reveals a function in post-translational modification crosstalk
Authors: You Youngki , Tsai Chia-Feng , Patel Rishi , Sarkar Soumyadeep , Clair Geremy , Zhou Mowei , Liu Tao , Metz Thomas O. , Das Chittaranjan , Nakayasu Ernesto S. 
Published: September 2023

Abstract
Background
Lysine carbamylation is a biomarker of rheumatoid arthritis and kidney diseases. However, its cellular function is understudied due to the lack of tools for systematic analysis of this post-translational modification (PTM).

Methods
We adapted a method to analyze carbamylated peptides by co-affinity purification with acetylated peptides based on the cross-reactivity of anti-acetyllysine antibodies. We also performed immobilized-metal affinity chromatography to enrich for phosphopeptides, which allowed us to obtain multi-PTM information from the same samples.

Results
By testing the pipeline with RAW 264.7 macrophages treated with bacterial lipopolysaccharide, 7,299, 8,923 and 47,637 acetylated, carbamylated, and phosphorylated peptides were identified, respectively. Our analysis showed that carbamylation occurs on proteins from a variety of functions on sites with similar as well as distinct motifs compared to acetylation. To investigate possible PTM crosstalk, we integrated the carbamylation data with acetylation and phosphorylation data, leading to the identification 1,183 proteins that were modified by all 3 PTMs. Among these proteins, 54 had all 3 PTMs regulated by lipopolysaccharide and were enriched in immune signaling pathways, and in particular, the ubiquitin-proteasome pathway. We found that carbamylation of linear diubiquitin blocks the activity of the anti-inflammatory deubiquitinase OTULIN.

Conclusions
Overall, our data show that anti-acetyllysine antibodies can be used for effective enrichment of carbamylated peptides. Moreover, carbamylation may play a role in PTM crosstalk with acetylation and phosphorylation, and that it is involved in regulating ubiquitination in vitro.

Graphical Abstract
Exo-miR-1290-induced by COX-2 overexpression promotes cancer-associated fibroblasts activation and tumor progression by CUL3-Nrf2 pathway in lung adenocarcinoma
Authors: Bai Xiaoming , Shao Jiaofang , Duan Tinghong , Liu Xue , Wang Min , Li Xuanya , You Qiang , Zhang Zhiyuan , Pan Jinshun 
Published: September 2023

Abstract
Background
Cancer-associated fibroblasts (CAFs) are critically involved in tumor progression by maintaining extracellular mesenchyma (ECM) production and improving tumor development. Cyclooxygenase-2 (COX-2) has been proved to promote ECM formation and tumor progression. However, the mechanisms of COX-2 mediated CAFs activation have not yet been elucidated. Therefore, we conducted this study to identify the effects and mechanisms of COX-2 underlying CAFs activation by tumor-derived exosomal miRNAs in lung adenocarcinoma (LUAD) progression.

Methods
As measures of CAFs activation, the expressions of fibroblasts activated protein-1 (FAP-1) and α-smooth muscle actin (α-SMA), the main CAFs markers, were detected by Western blotting and Immunohistochemistry. And the expression of Fibronectin (FN1) was used to analyze ECM production by CAFs. The exosomes were extracted by ultracentrifugation and exo-miRNAs were detected by qRT-PCR. Herein, we further elucidated the implicated mechanisms using online prediction software, luciferase reporter assays, co-immunoprecipitation, and experimental animal models.

Results
In vivo, a positive correlation was observed between the COX-2 expression levels in parenchyma and α-SMA/FN1 expression levels in mesenchyma in LUAD. However, PGE2, one of major product of COX-2, did not affect CAFs activation directly. COX-2 overexpression increased exo-miR-1290 expression, which promoted CAFs activation. Furthermore, Cullin3 (CUL3), a potential target of miR-1290, was found to suppress COX-2/exo-miR-1290-mediated CAFs activation and ECM production, consequently impeding tumor progression. CUL3 is identified to induce the Nuclear Factor Erythroid 2–Related Factor 2 (NFE2L2, Nrf2) ubiquitination and degradation, while exo-miR-1290 can prevent Nrf2 ubiquitination and increase its protein stability by targeting CUL3. Additionally, we identified that Nrf2 is direcctly bound with promoters of FAP-1 and FN1, which enhanced CAFs activation by promoting FAP-1 and FN1 transcription.

Conclusions
Our data identify a new CAFs activation mechanism by exosomes derived from cancer cells that overexpress COX-2. Specifically, COX-2/exo-miR-1290/CUL3 is suggested as a novel signaling pathway for mediating CAFs activation and tumor progression in LUAD. Consequently, this finding suggests a novel strategy for cancer treatment that may tackle tumor progression in the future.
Screening utility and acceptability of the Kiswahili-pGALS (paediatric Gait, Arms, Legs, Spine) at a tertiary referral hospital in Kenya-A diagnostic accuracy study
Authors: Kawishe Jacqueline E. , Ngugi Anthony , Luchters Stanley , Foster Helen , Migowa Angela 
Published: September 2023

Abstract
Background
Paediatric rheumatic diseases cause considerable disease burden to children and their families (Moorthy LN, Peterson MGE, Hassett AL, et al, Pediatric Rheumatology 8:20, 2010). Delayed diagnosis is a significant determinant of severity and mortality attributed to these conditions (Foster HE, Eltringham MS, Kay LJ, et al, Arthritis Care Res 57(6):921-7, 2007). pGALS is a simple clinical tool used to assess joints and identify musculoskeletal (MSK) conditions in school-going children to enable early referral to paediatric rheumatologists.

Objectives
This study aimed to translate and determine the diagnostic accuracy and acceptability of a Kiswahili version of the pGALS screening tool among Kiswahili-speaking children.

Methods
The pGALS screening questions were translated into Kiswahili according to the World Health Organisation (WHO) standard for translation of a tool. The validity of the Kiswahili PGALS was ascertained and acceptability rated (time taken, discomfort). Using systematic random sampling, we enrolled children aged 5–16 years presenting at the Aga Khan University Hospital’s (AKUH) emergency department in Kenya, who spoke Kiswahili and had symptoms suggestive of an MSK condition. Those already under follow-up at the paediatric rheumatology service at AKUH were excluded. MSK assessment was undertaken by two resident doctors using the newly translated Kiswahili-pGALS and findings were compared with a paediatric rheumatologist examination (‘gold-standard’) on the same day, and who was blinded to the pGALS findings. We analysed demographic details of the participants and determined the diagnostic accuracy by cross tabulation of the index test results by the results of the reference standard.

Results
One hundred children with a median age of nine years (IQR 7–11) were enrolled. The sensitivity and specificity of the Kiswahili-pGALS screening tool were 76.8% (95%CI 63.6–87.0%) and 40.0% (95%CI 23.9–57.9%), respectively. The diagnostic accuracy was 62.7% (95%CI 52.1–72.1%), area under the ROC was 0.58 (95%CI 0.48–0.68). The median time to perform the Kiswahili-pGALS was 5.0 min (IQR 3.5–6.0 min). Ninety percent of the guardians found the practice of Kiswahili-pGALS to have none, or only some discomfort.

Conclusions
The Kiswahili-pGALS’s was found to be a useful screening tool to aid early identification of MSK conditions in Kiswahili-speaking settings. However, the low specificity implies that relatively large number of false positives would still need to be reviewed by a rheumatologist if the tool is adapted for use.
Clinical presentation of human monkeypox virus infection during the 2022 outbreak: descriptive case series from a large italian Research Hospital
Authors: Salvo Pierluigi Francesco , Farinacci Damiano , Lombardi Francesca , Ciccullo Arturo , Tamburrini Enrica , Santangelo Rosaria , Borghetti Alberto , Di Giambenedetto Simona 
Published: September 2023

Abstract
Background
In May 2022, a new case of Monkeypox Virus (MPX) was reported in a non-endemic area, the United Kingdom, and since then, the number of confirmed cases in Europe has been increasing until WHO, on May 10 2023, declared that MPOX is no longer a public health emergency of international concern. We aimed to describe the clinical and microbiological characteristics of sixteen patients with a confirmed diagnosis of MPX followed by a single Italian clinical centre, the Fondazione Policlinico Universitario Agostino Gemelli, between May 20 and August 30.

Materials and methods
A prospective observational study has been conducted, collecting microbiological samples during the time of the infection, as well as epidemiological and clinical data of the patients. All patients provided written informed consent.

Results
During clinical practice, 16 individuals presenting with consistent symptoms tested positive for MPX on a polymerase chain reaction. All patients were men having sex with men (MSM). The most frequent clinical presentation was a vesicular erythematous cutaneous rash, mainly distributed on the genital and perianal area, but also regarding limbs, face, neck, chest and back in some of the patients. Systemic symptoms, such as fever or lymphadenopathy, involved eight patients. The symptom most frequently reported by patients was pruritus in the area of the vesicles. Thirteen patients also reported pain. Nine patients were HIV-1 coinfected, but no significant differences have been observed compared to other cohort patients. The median time between the onset of symptoms and the healing was 19.5 days (IQR 14.0–20.3).

Conclusions
Our cohort of patients presented a mild manifestation of the disease with no complications and no need for antiviral therapy nor hospitalization. This population seems different from the ones reported in the literature during the previous outbreaks in endemic areas in epidemiological data and clinical manifestations but also from a cohort of patients described in the literature from the 2022 outbreak, suggesting the importance for healthcare workers to keep in mind the possibility of an MPX infection in the differential diagnosis of patients presenting with consistent symptoms, even in non-endemic areas, to ensure efficient isolation of the patient for infection control purposes and effective management of the infection preventing the development of MPOX-related complications.
Clinical application of modified hip joint lateral position in femoral neck fracture
Authors: Liu Haitian , Gao Enpeng , Zhong Zhiwei , Wu Wenjuan , Zhang Zuzhuo 
Published: September 2023

Abstract
Background
To show the femoral neck better in hip lateral view of X-ray, we design a modified hip lateral view and then investigate the value in femoral neck fractures.

Methods
CT images of 10 normal hip joints for 3D reconstruction were selected, the Mimics Medical 21.0 was used, and rotating the proximal femur was to find the most suitable angle for showing the femoral neck well, designed the modified lateral view according to this angle. We collected 35 healthy cases and 35 femoral neck fractures as the normal and fracture group. And two groups were all taken hip anteroposterior view, cross-table lateral view and modified lateral view, which were analyzed by two radiologists to score the anatomical structures of the articular surface, femoral head, head neck junction, femoral neck, basal region and intertrochanteric region. Friedman test was used to analyze the score of femoral neck at different angles. T test and Wilcoxon signed-rank test were to compare inter-groups.

Results
The modified lateral view was designed as follows: The subjects were supine, with the sagittal axis biased toward the healthy side at an angle of approximately 20° to the long axis of the examination table, the hip joint flexed at 45°, the lower extremity abducted at 40°, the centerline inclined 45° toward the head and the centerline aligned with the center of the groin. The modified lateral view showed the femoral head, head neck junction and femoral neck more clearly than the cross-table lateral view, but the cross-table lateral view showed the femoral neck basal and intertrochanteric region better. In addition, the time of taking the modified lateral view was significantly less than the cross-table lateral view (normal group: 0.789 min ± 0.223 vs 0.623 min ± 0.207, P < 0.001; fracture group: 1.131 min ± 0.362 vs 0.946 min ± 0.390, P < 0.001).

Conclusions
The modified lateral view can obtain a standard sagittal image of femoral neck, which can show the dislocation and angulation of the sagittal femoral neck fracture clearly, and improve the accuracy of diagnosis. And it is more convenient and easier for patients to cooperate, which is worthy promoting and applying in clinical work.
Non-weight-bearing exercise attenuates papain-induced knee osteoarthritis in rats via the TLR4/MyD88/NF-κB signaling pathway
Authors: Wang Kewen , Zhang Xianji , Li Xin , Li Dekun , Shan Ziliang , Yao Changfeng 
Published: September 2023

Abstract
Background and Aim
Knee osteoarthritis (KOA) is characterized by joint wear and degeneration. Unfortunately, the medical community currently lacks effective treatment options for this disease. Suspension exercise therapy is considered an effective form of non-weight-bearing exercise for treating KOA. However, its mechanism of intervention in KOA is unclear. Therefore, this study aimed to evaluate the protective effects of non-weight-bearing exercise on rats with KOA and attempted to explore the underlying mechanisms.

Methods
In this study, a papain-induced KOA model was constructed, and the pathological changes in cartilage tissue were observed by hematoxylin and eosin (H&E) staining and scored according to the Mankin scoring principle. The serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay. Reverse transcription–quantitative polymerase chain reaction and Western blotting were used to detect the expression of mRNA and proteins in the TLR4/MyD88/NF-κB signaling pathway.

Results
H&E staining and Mankin score data confirmed that non-weight-bearing exercise significantly improved articular cartilage degradation compared with that in the model group. Further, we observed that non-weight-bearing exercise differentially reduced serum levels of IL-1β, IL-6, and TNF-α. Mechanistically, non-weight-bearing exercise downregulated gene and protein expression of TLR4, MyD88, and NF-κB in cartilage tissue.

Conclusion
Non-weight-bearing exercise resulted in the progression of KOA by modulating the TLR4/MyD88/NF-κB signaling pathway and decreasing the levels of the inflammatory cytokines IL-1β, IL-6, and TNF-α to slow down the degeneration of articular cartilage.
Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence
Authors: Zhang Shuming , Yuan Long , Danilova Ludmila , Mo Guanglan , Zhu Qingfeng , Deshpande Atul , Bell Alexander T. F. , Elisseeff Jennifer , Popel Aleksander S. , Anders Robert A. , Jaffee Elizabeth M. , Yarchoan Mark , Fertig Elana J. , Kagohara Luciane T. 
Published: September 2023

Abstract
Background
Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy.

Methods
We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection.

Results
ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient.

Conclusions
These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.
The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants—a multi-site prospective cohort study
Authors: Davidson Aimee L. , Dressel Uwe , Norris Sarah , Canson Daffodil M. , Glubb Dylan M. , Fortuno Cristina , Hollway Georgina E. , Parsons Michael T. , Vidgen Miranda E. , Holmes Oliver , Koufariotis Lambros T. , Lakis Vanessa , Leonard Conrad , Wood Scott , Xu Qinying , McCart Reed Amy E. , Pickett Hilda A. , Al-Shinnag Mohammad K. , Austin Rachel L. , Burke Jo , Cops Elisa J. , Nichols Cassandra B. , Goodwin Annabel , Harris Marion T. , Higgins Megan J. , Ip Emilia L. , Kiraly-Borri Catherine , Lau Chiyan , Mansour Julia L. , Millward Michael W. , Monnik Melissa J. , Pachter Nicholas S. , Ragunathan Abiramy , Susman Rachel D. , Townshend Sharron L. , Trainer Alison H. , Troth Simon L. , Tucker Katherine M. , Wallis Mathew J. , Walsh Maie , Williams Rachel A. , Winship Ingrid M. , Newell Felicity , Tudini Emma , Pearson John V. , Poplawski Nicola K. , Mar Fan Helen G. , James Paul A. , Spurdle Amanda B. , Waddell Nicola , Ward Robyn L. 
Published: September 2023

Abstract
Background
Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer.

Methods
This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken.

Results
Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing.

Conclusions
These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.
Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study
Authors: Baraliakos Xenofon , van der Heijde Désirée , Sieper Joachim , Inman Robert D. , Kameda Hideto , Li Yihan , Bu Xianwei , Shmagel Anna , Wung Peter , Song In-Ho , Deodhar Atul 
Published: September 2023

Abstract
Background
Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study.

Methods
Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported.

Results
Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population.

Conclusions
Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure.

Trial registration
NCT02049138.
Dynamic access control method for SDP-based network environments
Authors: You Hyunjin , Ko Doochan , Kim Daniel , Wong Richard , Joe Inwhee 
Published: September 2023

AbstractWith online work environments and other distributed computing systems—such as cloud technologies or Internet of Things systems—becoming increasingly popular today due to the COVID-19 pandemic and general technological advances, the question of how to keep them secure has also become a pertinent concern. With this increased dependence on online systems for companies, cyberattacks have also been on the rise. To protect terminal devices, many companies have resorted to implementing a single boundary-defense model. This method has yielded positive results in securing the network from external threats, but it does not effectively protect network from internal security threats. With the vulnerabilities in the internal network security in mind, a dynamic access control method used with a zero-trust software-defined perimeter security model could be a viable solution. This study proposes a dynamic access control method using an engine with a new reward and penalty point-based system (RP Engine) and a dynamic task engine (DT Engine) for a zero-trust SDP security model.