bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of lncRNA CBR3-AS1 for patients with cancer: A meta-analysis
Authors: Peng Jun , Wang Daidong , Liu Shixue
Published: November 2024

Background:

Several studies have shown that the long noncoding RNA (lncRNA) CBR3-AS1 is overexpressed in various cancers and is playing an oncogene role. This meta-analysis aims to elucidate the relationship between lncRNA CBR3-AS1 expression and the prognosis and clinicopathological features of cancer patients.

Methods:

A comprehensive and systematic search was conducted in PubMed, Web of Science, Cochrane Library, and EMBASE database. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were employed to evaluate the association between lncRNA CBR3-AS1 expression and clinical outcomes and clinicopathological features in cancer patients.

Results:

This meta-analysis finally enrolled 9 studies comprising 800 cancer patients. The combined results indicated that lncRNA CBR3-AS1 overexpression was significantly associated with shorter overall survival (pooled hazard ratios = 1.69, 95% CI 1.28–2.21, P < .001). Furthermore, elevated lncRNA CBR3-AS1 expression was closely correlated with larger tumor size (large vs small OR = 2.17, 95% CI: 1.50–3.14, P < .0001), lymph node metastasis (yes vs no OR = 2.75, 95% CI: 1.67–4.51, P < .0001), distant metastasis (yes vs no OR = 3.08, 95% CI: 1.82–5.23, P < .0001), and advanced tumour, node, metastasis stage (III/IV vs I/II OR = 2.82, 95% CI: 1.68–4.75, P < .0001).

Conclusion:

Upregulated expression of lncRNA CBR3-AS1 showed significant association with unfavorable survival and indicated worse clinicopathological outcomes in multiple kinds of human cancer, and therefore might serve as a promising prognosis biomarker and therapeutic target for cancers.
The effect of CYP2R1 polymorphism (rs10741657) on serum lipid traits in a Han septic population: A case-control study
Authors: Lin Zhao , Zhou Jun , Wang Siting , Fan Yipan , Li Xiang , Zhang Ning
Published: November 2024

Vitamin D deficiency has been proven to be associated with dyslipidemia. Additionally, the synthesis of vitamin D depends on cytochrome P450 2R1 (CYP2R1). However, the relationship between CYP2R1 polymorphisms and lipid metabolism has shown inconsistent results. A case-control study was conducted in a Han Chinese population, including 92 septic patients and 92 polytrauma patients. Based on serum lipid levels, 28 septic patients were further divided into a hyperlipidemia group, while 64 were placed in the control group; similarly, 34 polytrauma patients were categorized into a hyperlipidemia group and 58 into the control group. Genotyping of CYP2R1-rs10741657 was performed and serum lipid levels were measured. The Genotype-Tissue Expression project was used to assess expression quantitative trait loci for CYP2R1 mRNA expression and rs10741657. The genetic analyses revealed that the G-allele of CYP2R1-rs10741657 was significantly associated with an increased risk of hyperlipidemia in both sepsis (OR = 2.333, 95% CI: 1.227–4.436, P = .010) and polytrauma groups (OR = 4.000, 95% CI: 2.048–7.811, P < .001). Further analysis indicated that the rs10741657 mutation was mainly linked to higher serum high-density lipoprotein cholesterol levels in controls (P < .05). In functional analysis of rs10741657, the mutation was found to be associated with high CYP2R1 mRNA expression in whole blood from expression quantitative trait loci data (P = 3.53 × 10−9). In conclusion, the G-allele of CYP2R1-rs10741657 could elevate high-density lipoprotein cholesterol levels and protect against sepsis development.
Treatment outcomes and healthcare resource utilization in critically ill COVID-19 patients in Korea: A nationwide multicenter cohort study
Authors: Kim Taehwa , Kim Jeong Su , So Min Wook , Yeo Hye Ju , Jang Jin Ho , Park Onyu , Cho Woo Hyun ,   On behalf of Korean Intensive Care Study Group
Published: November 2024

COVID-19 pandemic was accompanied by many healthcare-related issues. Concrete national data regarding the care performance of critical ill cases of COVID-19 does not exist in Korea. The current study aimed to describe the treatment outcome and healthcare resource utilization of critically ill COVID-19 patients. Our multicenter retrospective cohort study enrolled critically ill COVID-19 patients from 22 tertiary care hospitals in Korea. Inclusion criteria: (1) patients aged 19 years or older, (2) patients with laboratory-confirmed SARS-CoV-2 infection who received at least one of following initial treatments such as high-flow oxygen therapy (HFOT) or noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation. During the study wave, a total of 1358 eligible participants were enrolled, with 21 institutions participating in the study. Among them, data from 1113 patients were available and analyzed. Of 921 (82.7%), 621 (55.8%) were supported by IMV. Of the 921 patients supported by HFOT or NIV, 438 (47.6%) recovered without IMV, 429 (46.6%) required IMV, and 54 died who DNR after NIV was applied. Prone position ventilation was administered to 163 (33.1%) patients with IMV and 25 (6.2%) patients with HFOT. Extracorporeal membrane oxygenation was administered to 128 (20.6%) patients treated with IMV. The overall mortality rate was 26.4%. In South Korea, mortality rates for patients with severe COVID-19 pneumonia have been shown substantial fatality, with the highest mortality rates observed in wave 3. The increased mortality rate in wave 3 could be associated with the rapid escalation of critically ill COVID-19 patients and the consequent saturation of intensive care unit capacities. Patients received NIV therapy and prone position ventilation more frequently in wave 3 as the number of cases increased.
Safety of baricitinib 24 weeks 4 mg or 2 mg for the treatment of rheumatoid arthritis: A meta-analysis of randomized controlled trials
Authors: Shi Zhihua , Cai Junlong , Yang Ling , Tang Lizhi , She Lang
Published: November 2024

Backgrounds:

Baricitinib, an oral selective inhibitor of Janus kinase 1 and 2, is approved for moderate and severe rheumatoid arthritis (RA) with insufficient response to conventional synthetic disease-modifying antirheumatic drugs. The study evaluated the safety of baricitinib 24 weeks 4 mg or 2 mg for the treatment of RA.

Methods:

The net change (least squares mean [LSM]) of alanine aminotransferase (ALT), creatinine, low-density lipoprotein cholesterol (LDL-C) levels from baseline with the comparison of baricitinib versus placebo was pooled, respectively. The risk ratios (RR) of serious advanced events (SAEs), major cardiovascular events (MACEs), infection, serious infection, and advanced events (AEs) at the end of treatment across groups were compared.

Results:

Five randomized controlled trials with 2901 patients were included in the summary analysis. Results showed that baricitinib 4 mg significantly increased ALT and creatinine levels, the net LSM change was respectively 3.59 U/L with 95% confidence interval (CI) (1.75–5.43), 4.25 µmol/L with 95% CI (3.38–5.12), however, baricitinib 2 mg of ALT and creatinine levels were not significantly different. Baricitinib 4 mg and 2 mg significantly increased LDL-C levels, the net LSM change was respectively 11.44 mg/dL with 95% CI (6.08–16.80), 8.70 mg/dL with 95% CI (4.19–13.20). Baricitinib 4 mg significantly increased the incidence of infection, the pooled RR (95% CI) was 1.29 (1.13–1.47), and baricitinib 2 mg was not significantly different. However, the pooled RRs of SAEs, MACEs, and serious infection were not statistically significant across groups. The pooled RRs of AEs were not statistically significant between baricitinib 4 mg and 2 mg.

Conclusions:

This study confirmed that patients with RA taking 4 mg baricitinib increased levels of ALT, creatinine, as well as an increased risk of infections, compared with those taking 2 mg baricitinib. Both 2 mg and 4 mg also increased the level of LDL-C, but it increased the most severely at 4 mg baricitinib. However, the incidence of SAEs, MACEs, and serious infection was not significantly different in patients treated with baricitinib 4 mg and 2 mg compared with placebo, the incidence of AEs was not significantly different between baricitinib 4 mg and 2 mg.
The causal relationship between gut microbiota and 2 neoplasms, malignant and benign neoplasms of bone and articular cartilage: A two-sample Mendelian randomization study
Authors: Lv Jia , Qin Xiuyu , Wang Jiani , Li Jian , Bai Junjun , Lan Yanping
Published: November 2024

Previous research has demonstrated a close connection between the development of bone neoplasms and variations in the abundance of specific gut microbiota. It remains unclear, however, how the gut microbiota and bone neoplasms are causally related. Hence, in our study, we aim to clarify this relationship between gut microbiota and 2 neoplasms, malignant neoplasm of bone and articular cartilage (MNBAC) and benign neoplasm of bone and articular cartilage (BNBAC), by employing a two-sample Mendelian randomization (MR) approach. In this study, single nucleotide polymorphisms (SNPs) from genome-wide association studies-pooled data related to bone neoplasms and gut microbiota abundance were evaluated. The inverse variance weighted was employed as the major method for assessing the aforementioned causal relationship. Furthermore, the horizontal multiplicity was evaluated utilizing the Mendelian randomization pleiotropy residual sum and outlier and the MR-Egger intercept test. Finally, inverse MR analysis was performed to assess reverse causality. Inverse variance weighted results indicate a potential genetic relationship between 4 gut microbiota and MNBAC, and 3 gut microbiota and BNBAC. On the one hand, Eubacterium eligens group (OR = 0.16, 95% CI = 0.04–0.67, P = .01), Odoribacter (OR = 0.23, 95% CI = 0.06–0.84, P = .03), Slackia (OR = 0.35, 95% CI = 0.13–0.93, P = .04), and Tyzzerella3 (OR = 0.44, 95% CI = 0.24–0.82, P = .01) exhibited a protective effect against MNBAC. On the other hand, of the 3 gut microbes identified as potentially causally related to BNBAC, Oscillibacter (OR = 0.79, 95% CI = 0.63–0.98, P = .03) and Ruminococcus torques group (OR = 0.62, 95% CI = 0.39–0.98, P = .04) were regarded as protective strains of B, while Eubacterium ruminantium group (OR = 1.24, 95% CI = 1.04–1.47, P = .02) was considered to be a risk factor for increasing the incidence of BNBAC. Additionally, the bone neoplasms were not found to have a reverse causal relationship with the above 7 gut microbiota taxa. Four gut microbiota showed causal effects on MNBAC, and 3 gut microbiota demonstrated causality in BNBAC, providing insights into the design of future interventions to reduce the burden of neoplasms.
Platelet-rich plasma: A bibliometric and visual analysis from 2000 to 2022
Authors: Du Kai , Li Ao , Zhang Chen-Yu , Guo Ren , Li Shu-Ming
Published: November 2024

Background:

Platelet-rich plasma (PRP) is an integral biotherapeutic modality with evolving significance in the medical domain. Despite its expanding applications, a comprehensive bibliometric evaluation is essential to understand its development and impact.

Methods:

The Web of Science core collection subject search identified articles pertinent to PRP applications. Analytical tools, including CiteSpace, VOSviewer, Bibliometrix (R-Tool for R-Studio), TBtools, SCImago Graphica, Origin, and Excel, facilitated the bibliometric scrutiny. This examination spanned dimensions ranging from geographical and institutional contributions to thematic shifts and keyword prevalence.

Results:

A corpus of 5167 publications was analyzed, with the United States, particularly the Hospital for Special Surgery, emerging as major contributors. The American Journal of Sports Medicine was identified as the primary journal, and Anitua Eduardo as the leading author in the domain. Keyword analysis highlighted evolving research themes, with a shift from traditional applications in orthopedics and dentistry to emerging areas such as dermatology, aesthetics, and chronic pain management.

Conclusion:

The bibliometric analysis of PRP research reveals a multifaceted array of applications across various medical disciplines and highlights areas requiring further exploration, particularly in standardization, personalization, and safety. Future advancements in PRP research will necessitate innovative exploration, ethical considerations, and rigorous scientific validation to fully harness the therapeutic potential of PRP and related therapies.
Trends and implications of antimicrobial resistance in Pseudomonas aeruginosa: Insights from a 19-year study in Zhejiang Province
Authors: Li Ju , Wang Yunkang , Liu Pei , Zhang Yuanqing , Yang Yufan , Zhao Shuang , He Junfeng , Zhao Cheng , Jia Xu , Zhang Lin
Published: November 2024

This study aimed to elucidate the resistance trends of P. aeruginosa isolates from 2005 to 2023 in Zhejiang Province, emphasizing the impact of Coronavirus disease 2019 (COVID-19) on antimicrobial resistance patterns and clinical management. We retrospectively analyzed 7326 P. aeruginosa isolates collected from diverse clinical sources in a tertiary hospital in Zhejiang Province from 2005 to 2023. Identification and antibiotic susceptibility testing of each isolate were performed using the VITEK-32 automated system and the disk diffusion method, following Clinical and Laboratory Standards Institute guidelines. We assessed resistance patterns for key antibiotic classes relevant to P. aeruginosa treatment, including carbapenems, β-lactams, aminoglycosides, and quinolones. Statistical analyses, including trend evaluations and resistance determinant assessments, were conducted in R software (version 4.2.2), with visualizations generated through ggplot2 to illustrate resistance trends over time. This study focused on key anti-pseudomonal agents including carbapenems (imipenem and meropenem), β-lactams (piperacillin), and quinolones (ciprofloxacin and levofloxacin). We observed a progressive increase in resistance to imipenem from 6.8% in 2005 to 48.2% in 2023 and meropenem from 25.4% to 44.2% over the same period. Conversely, resistance rates to aminoglycosides declined, with gentamicin resistance dropping from 22.0% in 2005 to 5.0% in 2019. Cephalosporins exhibited variable trends, with cefepime resistance peaking at 40.4% in 2013 before declining to 12.1% in 2023. The findings indicated a progressive increase in resistance rates for these antibiotics, with notable peaks coinciding with changes in clinical practices and the COVID-19 pandemic. The analysis demonstrated that shifts in prescription habits, particularly during the COVID-19 pandemic, influenced resistance patterns, underscoring the need for context-specific antimicrobial stewardship strategies. This study identifies significant, evolving resistance patterns in P. aeruginosa over a 19-year period, with marked increases in resistance to critical antibiotics, including carbapenems (imipenem, meropenem), quinolones (levofloxacin, ciprofloxacin), and certain β-lactams (piperacillin). These findings underscore an urgent need for dynamic, tailored infection control measures, emphasizing the importance of robust antibiotic stewardship programs, localized treatment guidelines, and proactive monitoring of resistance trends. Implementing these strategies is essential to effectively counter the challenges posed by multi-drug resistant P. aeruginosa, improve patient outcomes, and sustain the efficacy of vital antibiotic therapies.
The National Emergency Department Overcrowding Scale and Perceived Staff Workload
Authors: McKinley Kenneth W. , Bregstein Joan S. , Perotte Rimma , Fenster Daniel , Kwok Maria , Rose Jake , Nye Megan , Sonnett Meridith , Kessler David O.
Published: November 2024

Objective

The aim of the study is to determine if there is a correlation between perceived staff workload, measured by the NASA Task Load Index (TLX), and the National Emergency Department Overcrowding Scale (NEDOCS) in a pediatric ED.

Methods

We collected staff questionnaires in a large, urban pediatric ED to assess perceived workload on each of six different TLX subscales, which we weighted evenly to create an overall estimate of workload. We evaluated the correlation between individual TLX responses and NEDOCS overall and by staff subgroup. Additionally, we analyzed: (1) the correlation between mean TLX responses and NEDOCS within a given hour and (2) the performance of a logistic regression model, using TLX as a predictor for “severely overcrowded,” as measured by NEDOCS.

Results

Four hundred one questionnaires between 6/2018 and 1/2019 demonstrated significant variation between concurrently collected TLX responses and an overall poor correlation between perceived workload and NEDOCS (R
2 0.096 [95% confidence interval, 0.048–0.16]). TLX responses by subgroups of fellows (n = 4, R
2 0.96) and patient financial advisors (n = 15, R
2 0.58) demonstrated the highest correlation with NEDOCS. Taking mean TLX responses within a given hour, during periods with NEDOCS >60 (extremely busy or overcrowded), a polynomial trend line matched the data best (R
2 0.638). On logistic regression, the TLX predicts “severely overcrowded” with an area under the curve of the receiver operating characteristic of 0.731.

Conclusions

NEDOCS does not have a strong correlation with individual responses on questionnaires of perceived workload for staff in a pediatric ED. NEDOCS, as a measure of overcrowding, may be better correlated with perceived workload during periods with elevated crowding or when interpreted categorically as yes/no “severely overcrowded”.
Immune Reconstitution After Total Parathyroidectomy and Forearm Transplantation in Chronic Renal Failure
Authors: Ren Tingting , Zhong Tao , Yang Fuhua , Liao Xuesong , Yang Mei , Ji Lingling , Guo Zonglin , Huang Jun
Published: November 2024

Objective:

To investigate the immune reconstitution after total parathyroidectomy and forearm transplantation in chronic renal failure.

Method:

Forty-three patients, accompanied with chronic renal failure and secondary hyperparathyroidism (SHPT) that hospitalized during January 2019 to 2021 and underwent total thyroidectomy and forearm transplantation were enrolled as observation group. Forty hemodialysis patients with chronic renal failure but without SHPT were selected as the hemodialysis group. In addition, fifty volunteers who underwent physical examination within the same period were chosen as a control group. The parathyroid hormone (iPTH), blood phosphorus, blood calcium, th22, Treg cells, and inflammatory factors were detected in the three groups.

Results:

The preoperative iPHT, serum phosphorus, and calcium levels in the observation group were higher than those in the control group and hemodialysis group (P<0.05), and the index values of the observation group at each time point after surgery were remarkably lower than those in pre-surgery (P<0.05). The preoperative Th22 and Th22/Treg in the observation group were higher, and Treg was lower than those in the control group and hemodialysis group (P<0.05); The levels of Th22 and Th22/Treg in the observation group at each time point in post-operation were lower than those in pre-operation (P<0.05), whereas Treg cells in observation group at each time point postoperatively were higher than those prior-operation (P<0.05). The preoperative serum TNF-α, IL-6, TGF-β, and IL-22 in the observation group were notably higher than those in the control group and hemodialysis group (P<0.05); And TNF-α, IL-6, TGF-β, and IL-22 in observation group at each time point in post-operation were lower than those in pre-surgery(P<0.05).

Conclusion:

For chronic renal failure patients complicated with SHPT, total parathyroidectomy and forearm transplantation can effectively improve their clinical symptoms, reduce the inflammatory state of the body, and beneficial for immune reconstruction.
Competency, Proficiency, and Mastery
Authors: Müller Philip C. , Kuemmerli Christoph , Billeter Adrian T. , Shen Baiyong , Jin Jiabin , Nickel Felix , Guidetti Cristiano , Kauffmann Emanuele , Purchla Julia , Tschuor Christoph , Krohn Paul Suno , Burgdorf Stefan K. , Jonas Jan Philipp , Bussmann Felix J. , Saint-Marc Olivier , Iben-khayat Abdallah , Andel Paul C.M. , Molenaar Izaak Quintus , Wellner Ulrich , Keck Tobias , Moeckli Beat , Toso Christian , Di Benedetto Fabrizio , Valle Valentina , Giulianotti Pier , Roulin Didier , Martinie John B. , Rama Martina , Lavu Harish , Yeo Charles , Mavani Parit T. , Shah Mihir M. , Kooby David A. , He Jin , Boggi Ugo , Hackert Thilo , Borel-Rinkes Inne H.M. , Müller Beat P. , Clavien Pierre-Alain
Published: November 2024

Objective:

The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers.

Summary Background Data:

RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve.

Methods:

Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien–Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared.

Results:

The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications.

Conclusion:

Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP.
Exploring the druggability of the UEV domain of human TSG101 in search for broad-spectrum antivirals
Authors: Montero Fernando , Parra-López Marisa , Rodríguez-Martínez Alejandro , Murciano-Calles Javier , Buzon Pedro , Han Ziying , Lin L.-Y. , Ramos Maria C. , Ruiz-Sanz Javier , Martinez Jose C. , Radi Marco , Moog Christiane , Diederich Sandra , Harty Ronald N. , Pérez-Sánchez Horacio , Vicente Francisca , Castillo Francisco , Luque Irene
Published: November 2024

The ubiquitin E2 variant domain of TSG101 (TSG101-UEV) plays a pivotal role in protein sorting and virus budding by recognizing PTAP motifs within ubiquitinated proteins. Disruption of TSG101-UEV/PTAP interactions has emerged as a promising strategy for the development of host-oriented broad-spectrum antivirals with low susceptibility to resistance. TSG101 is a challenging target characterized by an extended and flat binding interface, low affinity for PTAP ligands, and complex binding energetics. Here, we assess the druggability of the TSG101-UEV/PTAP binding interface by searching for drug-like inhibitors and evaluating their ability to block PTAP recognition, impair budding, and inhibit viral proliferation. A discovery workflow was established combining in vitro miniaturized HTS assays and a set of cell-based activity assays including high-content bimolecular complementation, virus-like particle release measurement, and antiviral testing in live virus infection. This approach has allowed us to identify a set of chemically diverse molecules that block TSG101-UEV/PTAP binding with IC50s in the low μM range, and able to disrupt the interaction between full-length TSG101 and viral proteins in human cells and inhibit viral replication. State-of-the-art molecular docking studies reveal that the active compounds exploit binding hotspots at the PTAP binding site, unlocking the full binding potential of the TSG101-UEV binding pockets. These inhibitors represent promising hits for the development of novel broad-spectrum antivirals through targeted optimization and are also valuable tools for investigating the involvement of ESCRT in the proliferation of different virus families and study the secondary effects induced by the disruption of ESCRT/virus interactions.

Importance

Many viruses rely on the interaction between TSG101 and viral proteins containing PTAP motifs for their proliferation. Here we show that these interactions can be efficiently blocked by drug-like compounds that impair budding and replication of viruses from different families. We have also provided valuable insights into the determinants of high affinity for these small molecule inhibitors that open new avenues for developing the identified candidates into broad-spectrum antivirals with low susceptibility to resistance.
WITHDRAWN: Significantly enhancing antiviral efficacy by computational optimization and structural engineering of grafted nanobodies
Authors: Huo Liyun , Qin Qin , Tian Tian , Zhang Xing , He Xiaoming , Cao Yuhui , Zhang Tianfu , Xu Yanqin , Huang Qiang
Published: November 2024

Withdrawal Statement

The authors have withdrawn this manuscript because of incorrect figure legends and some typos in the main text. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
Physically Interpretable Performance Metrics for Clustering
Authors: Mondal Kinjal , Klauda Jeffery B.
Published: November 2024

Clustering is a type of machine learning (ML) technique which is used to group huge amounts of data based on their similarity into separate groups or clusters. Clustering is a very important task which is nowadays used to analyze the huge and diverse amount of data coming out of molecular dynamics (MD) simulations. Typically, the data from the MD simulations in terms of their various frames in the trajectory are clustered into different groups and a representative element from each group is studied separately. Now a very important question coming in this process is what is the quality of the clusters that are obtained. There are several performance metrics that are available in literature like Silhouette index and Davies-Bouldin Index that are often used to analyze the quality of clustering. However, most of these metrics focus on the overlap or the similarity of the clusters in the reduced dimension that is used for clustering and do not focus on the physically important properties or the parameters of the system. To address this issue, we have developed two physically interpretable scoring metrics that focus on the physical parameters of the system that we are analyzing. We have used and tested our algorithm on three different systems (1) Ising model, (2) peptide folding and unfolding of WT HP35, (3) a protein-ligand trajectory of an enzyme and substrate and (4) a protein-ligand dissociated trajectory. We show that the scoring metrics provide us clusters that match with our physical intuition about the systems.
Phenome-wide causal proteomics enhance systemic lupus erythematosus flare prediction: A study in Asian populations
Authors: Chen Liying , Deng Ou , Fang Ting , Chen Mei , Zhang Xvfeng , Cong Ruichen , Lu Dingqi , Zhang Runrun , Jin Qun , Wang Xinchang
Published: November 2024

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares. This study aimed to develop a novel proteomics-based risk prediction model specifically for Asian SLE populations to enhance personalized disease management and early intervention.

Methods

A longitudinal cohort study was conducted over 48 weeks, including 139 SLE patients monitored every 12 weeks. Patients were classified into flare (n = 53) and non-flare (n = 86) groups. Baseline plasma samples underwent data-independent acquisition (DIA) proteomics analysis, and phenome-wide Mendelian randomization (PheWAS) was performed to evaluate causal relationships between proteins and clinical predictors. Logistic regression (LR) and random forest (RF) models were used to integrate proteomic and clinical data for flare risk prediction.

Results

Five proteins (SAA1, B4GALT5, GIT2, NAA15, and RPIA) were significantly associated with SLE Disease Activity Index-2K (SLEDAI-2K) scores and 1-year flare risk, implicating key pathways such as B-cell receptor signaling and platelet degranulation. SAA1 demonstrated causal effects on flare-related clinical markers, including hemoglobin and red blood cell counts. A combined model integrating clinical and proteomic data achieved the highest predictive accuracy (AUC = 0.769), surpassing individual models. SAA1 was highlighted as a priority biomarker for rapid flare discrimination.

Conclusion

The integration of proteomic and clinical data significantly improves flare prediction in Asian SLE patients. The identification of key proteins and their causal relationships with flare-related clinical markers provides valuable insights for proactive SLE management and personalized therapeutic approaches.

Graphical Abstract
A PRDM16-CtBP1/2 Complex Interacts with HDAC1/2 to Regulate Transcriptional Programs of Neurogenesis and Guide Cortical Neuron Migration
Authors: Warren Sophie , Farran Bader El , Kang Sungyun , Choudhuri Adhyeta , Xiong Sen , Brendel Volker P. , Baizabal José-Manuel
Published: November 2024

Chromatin regulation of transcriptional enhancers plays a central role in cell fate specification and differentiation. However, how the coordinated activity of transcription factors and chromatin-modifying enzymes regulates enhancers in neural stem cells (NSCs) and dictates subsequent stages of neuronal differentiation and migration is not well understood. The histone methyltransferase PRDM16 is expressed in NSCs of the developing mouse and human cerebral cortex and is essential for determining the position of upper-layer cortical neurons. Here, we report that PRDM16 interacts with C-terminal binding protein 1 (CtBP1) and CtBP2 to control the transcriptional programs of cortical neurogenesis and regulate upper-layer neuron migration. PRDM16 and CtBP1/2 co-regulate enhancers by interacting with histone deacetylase 1 (HDAC1) and HDAC2, and lysine-specific demethylase 1 (LSD1). In addition, our results suggest that the CCCTC-binding factor CTCF plays a key role in recruiting CtBP1/2 to cortical enhancers. These findings underscore that reduced interactions between PRDM16 and ubiquitous chromatin regulators may contribute to neurodevelopmental deficits in patients withPRDM16haploinsufficiency.
Advancing Remote and Low-Resource Healthcare Delivery with Microbiopsy Skin Sample mRNA Housekeeping Gene Stability Analysis Across Various Temperatures
Authors: Nataren Nathalie , Gunnell Lucy , Prow Tarl W , Yamada Miko
Published: November 2024

In the clinical dermatology setting, conventional skin sampling methods such as punch, shave, or excision biopsy are invasive, requiring local anesthesia and after-procedure care. These methods also necessitate immediate processing and cold storage to preserve high-quality nucleic acid, limiting their use in remote and low-resource regions. The microbiopsy, a minimally invasive device designed for sub-millimetre skin sampling, offers an alternative that may overcome these limitations by providing genetic profiles from the viable epidermis.

We examined skin patient samples (5 microbiopsies, 3 individuals) stored across five conditions temperature conditions expected to be encountered during commercial shipping. RNA was extracted for TaqMan assay Real-Time PCR on the Fluidgim Dynamic Array targeting three housekeeping genes (ACTB, GAPDH, and RPLP0). Housekeeping genes were successfully detected at comparable levels in samples across non-control conditions, contrasting with positive control samples which showed a trend toward lower gene expression detection.

In conclusion, we have established that microbiopsy samples stored in the RNA preservation agent can withstand uncontrolled temperatures likely to be encountered during commercial shipping. This could have a significant impact on enabling access to molecular diagnostic testing in an era of increasing personalized medicine and to address the long-standing need to improve remote healthcare delivery.
Multi-purpose controllable protein generation via prompted language models
Authors: Wang Zeyuan , Chen Binbin , Ding Keyan , Cao Jiawen , Qin Ming , Niu Yadan , Zhuang Xiang , Li Xiaotong , Feng Kehua , Xu Tong , Zhang Ningyu , Yu Haoran , Zhang Qiang , Chen Huajun
Published: November 2024

Deep learning is increasingly powerful for designing proteins that meet structural and functional requirements. However, most existing methods follow a conventional pipeline: first defining a backbone structure and then generating sequences consistent with it. This approach, which encodes all design goals indirectly through structures, restricts flexibility and struggles to address multiple, complex design objectives simultaneously. We present PROPEND, a multi-purpose protein sequence design method based on the “pre-train and prompt” framework. We show PROPEND’s broad utility and accuracy bothin silicoandin vitroby directly controlling multiple properties through the prompt of backbones, blueprints, functional tags, and their combinations. For the five sequences tested within vitroexperiments, PROPEND achieved a maximum functional recovery of 105.2%, significantly outperforming the classical design pipeline’s 50.8%.
Sensitivity to climate change is widespread across zoonotic diseases
Authors: Trebski Artur , Gourlay Lewis , Gibb Rory , Imirzian Natalie , Redding David W.
Published: November 2024

Climate change is expected to exacerbate infectious diseases, yet the climate sensitivity of zoonotic diseases (driven by spillover from animal reservoirs) is markedly understudied compared to vector-borne and water-borne infections. To address this gap, we conducted a global systematic review and quantitative synthesis to identify relationships between climatic indicators (temperature, precipitation, humidity) and zoonotic disease risk metrics worldwide. We identified 185 studies from 55 countries, describing 547 measures across 51 diseases, with most studies testing linear (n=166) rather than nonlinear (n=23) relationships. We found evidence of climate sensitivity across diverse zoonotic diseases (significant non-zero relationships in 64.3% of temperature effects, 49.8% of precipitation effects, and 48.9% of humidity effects), but with broad variation in direction and strength. Positive effects of temperature and rainfall on disease risk were more common than negative effects (39.1% vs. 25.2% and 30.5% vs. 19.2% of all records, respectively). These studies were predominantly located in areas expected to have substantial increases in annual mean temperature (>1.5°C in 93% of studies) and rainfall (>25 mm in 46% of studies) by 2041–2070. Notably, the most consistent relationship was between temperature and vector-borne zoonoses (50% of Positive effects, mean Hedge’s g = 0.31). Overall, our analyses provide evidence that climate sensitivity is common across zoonoses, likely leading to substantial yet complex effects of future climate change on zoonotic burden. Finally, we highlight the need for future studies to use biologically appropriate models, rigorous space-time controls, consider causal perspectives and address taxonomic and geographic biases to allow a robust consensus of climate-risk relationships to emerge.

Significance statement

Understanding how climate change affects zoonotic diseases—those transmitted from animals to humans—is crucial for public health planning yet remains underexplored. Our global analysis of 185 studies covering 51 zoonotic diseases reveals widespread climate sensitivity among these diseases. Climatic factors, particularly temperature, are often linked to increased disease risk, especially for vector-borne diseases transmitted by arthropods. With many regions projected to experience significant warming, climate change may exacerbate zoonotic disease burden. However, few studies have considered nonlinear effects, and the variation in responses both within and across diseases indicates complex dynamics that require biologically informed research methods. These findings underscore the urgent need for improved research approaches to better predict and manage future disease risks in a changing climate.
The problem of unmeasured variables in animal social network analysis: can edge-based multilevel models provide a reliable solution?
Authors: Bonnell Tyler R. , Vilette Chloe , Barrett Louise
Published: November 2024

Recent approaches to analysing social networks suggest that modeling the edges of the network and using multilevel models will produce more informative estimates. These recent methods have been proposed as a way to better handle the dependency structures of social networks, account for biases in data collection, and retain uncertainty when making inferences about social network structures. We find that they have the potential to also effectively handle unmeasured variables that act as statistical confounds in social network analysis. Using simulated data, we highlight that static social network analyses can be used to identify patterns in social networks, but generally cannot be used to identify the underlying mechanisms behind the patterns. To identify mechanisms, we show that taking a dynamic approach and using edge-based models with additive and multiplicative random effects provides a means to identify mechanisms even when statistical confounds are present. Additive and multiplicative random effects also provide information about social structures not captured by the predictors, facilitating exploratory analysis. We suggest that a keep-it-maximal approach for random effects structures is beneficial for edge-based multilevel models of social networks, and that such approaches can be particularly effective when there are unmeasured variables that are not captured by model predictors.
Analysis of ribosomes from the Wild-type and FMR1 knockout human embryonic stem cells
Authors: Kharbanda Tripti , D’Souza Michelle Ninochka , Palakodeti Dasaradhi , Muddashetty Ravi S , Vinothkumar Kutti R.
Published: November 2024

Fragile X Messenger Ribonucleoprotein 1 (FMRP) is a multifunctional, multidomain RNA-binding protein whose loss causes Fragile X syndrome. It is also known to associate with ribosomes and modulate translation. In human embryonic stem cells (hESCs), knockout (KO) of the FMR1 gene results in significantly increased protein translation rates and alterations in the 2’-O-methylation patterns of rRNA. To understand the structural underpinnings of the process, we performed electron cryomicroscopy analysis of ribosomes isolated from both wild-type (WT) and FMR1 KO hESCs that revealed a subpopulation of dormant ribosomes in the FMR1 KO cells, in addition to ribosomes with tRNAs. This dormant subpopulation, absent in the WT hESCs, is characterized by the binding of SERPINE-mRNA binding protein 1 in the mRNA tunnel and eukaryotic elongation factor 2 near the A-site, preventing translation. The presence of elevated protein translation in FMR1 KO cells, alongside a subpopulation of inactive ribosomes, suggests that FMRP can function as a translational brake. However, due to the high cost of ribosome recycling, the cell appears to adopt a strategy of maintaining a subset of dormant ribosomes. Additionally, we analysed the 2’-O-methylation patterns in the 28S rRNA, in both the WT and FMR1 KO hESCs, identifying few potential differentially methylated sites. Thus, these findings provide insights into the mechanisms of ribosome dormancy in the absence of FMRP and lay the groundwork for understanding the role of rRNA methylation in translational regulation.
Back to the horns: a reconstruction of the ancestral horn state through distinct types of recombination events.
Authors: Upadhyay Maulik , Graf Alexander , pogorevc Neza , Seichter Doris , Russ Ingolf , Krebs Stefan , Meier Saskia , Medugorac Ivica
Published: November 2024

Background Breeding of the genetically polled animals is the desirable approach in modern cattle husbandry. At least four different genetic variants associated with polledness in cattle have been identified, suggesting genetic heterogeneity. These dominant variants have been identified on chromosome 1 between the regions of approx. 2.42 to 2.73 Mb (reference: ARS-UCD1.2), also called the POLLED locus. Among these variants, Friesian (PF, 80 kbp duplication) and Celtic (PC, 212 bp complex InDel) are the most observed in the majority of breeds in the production systems globally, such as in Holstein-Friesian (HF) and Fleckvieh (FV). While a putative causal association of PC with polledness is proven, the presence of large duplication in PF makes it difficult to prove the causality. Results In this study, we conduct whole-genome sequencing (WGS) analysis of two trios exhibiting unexpected inheritance patterns related to PC and PF variants. In both instances, horned offspring were produced from mating pairs where one parent was homozygous for the polled variant, and the other was homozygous for the ancestral horned variant. By analyzing the WGS data generated using long-read sequence technology, we show that de-novo generation of the ancestral horned variant in both the offspring was the result of distinct recombination events. Specifically, in case of the HF trio, it was the result of non-allelic homologous recombination in the gametes of the sire (PF/PF), while in case of the FV trio, it was the result of allelic homologous recombination in the gametes of the dam (PC/PF). The findings from the HF trio support the hypothesis that the 80-kbp duplication is the genetic variant responsible for the polled phenotype of Friesian origin. Conclusion Here we show that different genomic arrangements in POLLED locus can lead to the emergence of de-novo ancestral horn phenotypes. These kinds of arrangements can make a reliable gene test less reliable and the derivation of the phenotype difficult to predict. Therefore, it is important for the large POLLED-locus that any deviation from the expected result is critically analyzed. Possibly some of these cases can further narrow down the sequence motif that is essential for polledness in cattle.
Host-specific adaptation ofLegionella pneumophilato single and multiple hosts
Authors: Moreno Anaísa B. , Paranjape Kiran , Cederblom Martina , Kay Elisabeth , Dobre-Lereanu Christian , Andersson Dan I. , Guy Lionel
Published: November 2024

Legionella pneumophilais an endosymbiotic bacterial species able to infect and reproduce in various protist and human hosts. Upon entry in human lungs, they may infect lung macrophages, causing Legionnaires’ disease (LD), an atypical pneumonia, using similar mechanisms as in their protozoan hosts, despite the two hosts being separated by a billion years of evolution. In this study, we used experimental evolution to identify genes conferring host-specificity toL. pneumophila. To this end, we passagedL. pneumophilain two different hosts -Acanthamoeba castellaniiand the human macrophage-like cells U937 - separately and by switching between the hosts twice a week for a year. In total, we identified 1518 mutations present in at least 5% of the population at the time of sampling. Half of these were localized in five groups of repeated sequences, likely to be recombination hotspots. Forty-nine mutations were fixed in the 18 populations at the end of the experiment, representing four different groups. The first two groups involve adaptation to the specific selection conditions, including (i) two specific mutations in the 30S ribosomal protein S12 (RpsL) that conferred resistance to streptomycin, to which the bacteria were unexpectedly exposed to during serial passage and (ii) two mutations, one in the 30S ribosomal protein S4 (RpsD), and one in the chaperonin GroES, both of which are likely to be fitness-restoring compensatory mutations to the original RpsL mutations. Two more interesting groups of mutations included (iii) mutations in 4 different strain-specific genes involved in LPS synthesis, found only in the lineages passaged withA. castellaniiand (iv) mutations in the gene coding for LerC, a key regulator of protein effector expression, which was independently mutated in 6 lineages grown in presence of the U937 cells. We propose that the mutations degrading the function of the regulator LerC improve the fitness ofL. pneumophilain human-derived cells, and that modifications in the LPS are beneficial for growth inA. castellanii. This study is a first step in further investigating determinants of host specificity inL. pneumophila.
Development of optimised human iPSC-derived hepatocytes with improved liver function forin vitrometabolic disease modelling and toxicity studies
Authors: Łukasiak Magdalena , Gatti Gemma , Chung Samuel , Kiloh George , Robinson Chloe , Kasioulis Ioannis , Gil Carlos , Panman Lia , Nikolaou Nikolaos
Published: November 2024

Background & Aims

Liver disease is a rising cause of mortality worldwide. Primary human hepatocytes (PHH) and hepatocellular cancer cells are currently used in drug development, however, they come with limitations, including limited supply, rapid loss of function, and tumorigenic origin. In addition, current iPSC differentiation protocols lead to the generation of hepatocyte-like cells with compromised liver-related features. We hypothesised that optimisation of iPSC differentiation protocols can lead to the generation of hepatocyte-like cells with improved metabolic functionality for disease modelling and toxicity screening studies.

Methods

Healthy human iPSCs were differentiated to hepatocyte-like cells (Opti-HEP) using a novel 3-step differentiation protocol. Hepatocyte functionality was assessed, including liver maturity marker expression, urea synthesis,de novogluconeogenesis, and CYP450 expression, activity, and induction. Suitability of Opti-HEP to predict drug-induced liver injury (DILI) was evaluated by cell viability assays. CRISPR/Cas9 gene editing was employed to generatein vitroinherited metabolic disease models.

Results

Opti-HEP expressed similar liver maturity marker levels to those seen in primary human hepatocytes (PHH), in addition to functional urea and gluconeogenesis pathways. CYP450 expression and activity were comparable between Opti-HEP and PHH, with both cell types showing similar levels of CYP3A4 induction upon 1α,25-hydroxy-vitamin D3 treatment. Opti-HEP accurately predicted DILI, following treatment with 7 drugs of known DILI liability. CRISPR-derived Opti-HEP harbouring mutations for inherited metabolic disorders (Ornithine Transcarbamylase Deficiency, Progressive Familial Intrahepatic Cholestasis Type 2, Citrullinemia Type 1) recapitulated key pathophysiological disease features, including reduced protein expression, impaired urea secretion, and bile acid transport.

Conclusions

We demonstrate the generation of optimised iPSC-derived hepatocytes with enhanced liver functionality that is comparable to PHH. These data alongside the expansion capacity and amenability of these cells highlight the opportunities this model can offer in the space of disease modelling and large-scale drug efficacy and hepatotoxicity screening.