bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of Single-Sided Thoracic vs. Bilateral Thoracic and Lumbar Anterior Vertebral Body Tethering in Lenke 1 Curves with Lumbar C Modifier
Authors: Pahys Joshua M. , Samdani Amer F. , Quinonez Alejandro , Hwang Steven W.
Published: January 2025

Study Design:

Retrospective review of a prospectively collected single-center adolescent idiopathic scoliosis (AIS) database.

Objective:

To evaluate the outcomes of single-sided thoracic anterior vertebral body tethering (VBT) versus bilateral thoracic/thoracolumbar VBT for the treatment of Lenke 1C type curves, as well as the outcomes of Lenke 1A/B curves compared to 1C curves.

Background:

Lenke 1C curves can be successfully treated with selective thoracic fusion alone. However, there are few data to support whether this classification scheme holds true for VBT in Lenke 1C curves.

Materials and Methods:

A total of 242 consecutive AIS patients with Lenke 1 curves and a minimum two-year follow-up were grouped based on preoperative lumbar modifier A/B (n=163) or C (n=79). The total C group (CTot) was further subdivided into single-sided thoracic VBT (CSing, n=49) and bilateral thoracic and thoracolumbar VBT (CBil, n=30).

Results:

The preoperative lumbar Cobb angle was larger for CBil (47°) than for CSing (36°, P=0.04), but similar at two years postoperative (CBil, 19°; CSing, 19°). Patients with preoperative open triradiate cartilage (TRC) had significantly increased revision rates, primarily for overcorrection, in all groups (A/B, 38%; CSing, 29%; CBil, 89%; P=0.01), compared to preoperative closed TRC (A/B, 10%; CSing, 17%; CBil, 19%). A similar percentage of patients in both groups required subsequent fusion (A/B, 5% vs. CTot, 10%; P=0.1).

Conclusion:

The mean lumbar Cobb angle (19°) and percentage of patients with a lumbar Cobb angle > 35° (10%) were similar for CSing and CBil groups at the latest follow-up. Thus, performing a bilateral VBT did not significantly improve the postoperative lumbar curve magnitude compared with thoracic-only VBT (CSing) in our cohort. There was a non-significant difference in revision rates for A/B vs. C groups (18% vs. 28%), and CSing vs. CBil (20% vs. 40%). Revision rates were threefold higher in all patients with preoperative open TRC.
Using Technique and Technology to Improve Safety and Outcomes in AIS
Authors: Sarwahi Vishal , Eigo Katherine , Rahman Effat , Hasan Sayyida , Visahan Keshin , Lo Yungtai , DiMauro Jon-Paul , Amaral Terry
Published: January 2025

Study Design.

Retrospective Cohort Study.

Objective.

This study aimed to compare outcomes in AIS patients that underwent PSF using either freehand with occasional fluoroscopic assistance (FOFA), computer assisted surgery/navigation (CAS), or technique and technology (T&T).

Summary of Background Data.

Pedicle screw insertion in scoliosis is challenging due to abnormal pedicle morphology. Fluoroscopic guidance was frequently utilized, until technological advancements led to the adaptation of computer assisted screw insertion. While improvement in screw accuracy has been documented, an increase in radiation exposure, surgical time, and blood loss can occur. This institution adopted a T&T, or technique and technology, approach that combines freehand technique with CT-based navigation technology for confirmation and navigation for challenging pedicles.

Methods.

This was a two-part retrospective review of 573 AIS patients that underwent PSF.

Part I: 304 were operated in FOFA. 63 patients were operated on with solely CT-based navigation technology (CAS Group). 206 patients were in T&T. Perioperative outcomes were compared.

Part II: 206 T&T patients were compared to 326 AIS patients from the NSQIP database that were operated on using computer-assisted navigation (CAN). Operative time and 30-day complications were compared.

All data is presented as medians, IQR, frequencies, and percents. Fisher’s Exact, Chi-squared, Kruskal-Wallis, and Wilcoxon rank-sum tests were used.

Results.

FOFA radiation dose was 2.3 mGy and radiation time was 20.4 seconds compared to 22.2 mGy and 21.6 seconds for CAS, and 15.0 mGy and 18.6 seconds for T&T (P<0.001, P<0.001). Operative time was shorter for the T&T patients when compared to FOFA and CAS (P<0.001).

Part II: T&T had an operative time of 233.0 minutes compared to 323.0 minutes for CAN (P<0.001).

Conclusion.

T&T optimizes screw accuracy while reducing the increased radiation burden and operative time associated with CAS. The T&T approach incorporates CT-based navigation technology as confirmation, while maintaining surgeon’s skill.
Co-infection with hepatitis B and human immunodeficiency virus: epidemiology, pathogenesis, and treatment
Authors: He Yaozu , Lin Weiyin , Gu Fei , Lan Xianglong , Li Linghua
Published: January 2025

Co-infection with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is common as the modes of disease transmission are similar. HIV affects the development of chronic HBV infection, leading to higher HBV DNA levels, cirrhosis, and end-stage liver duisease, and potentially leading to hepatocellular carcinoma. One of the leading causes of mortality and morbidity in HIV-infected individualsis liver disease, despite the administration of antiretroviral therapy for HIV and HBV. Thus, the screening and follow-up of co-infected patients are vital formonitoring of liver disease progression. This study reviews the natural history and pathogenesis of liver disease in the context of HBV/HIV co-infection, current treatments for HBV in patients with HIV, and treatment outcomes in coinfected individuals.
Effect of a calcium-channel blocker and β-blocker combination on reading-to-reading blood pressure variability: a randomized crossover trial
Authors: Xia Jia-Hui , Cheng Yi-Bang , Xu Ting-Yan , Guo Qian-Hui , Chan Chak-Ming , Hu Lei-Xiao , Li Yan , Wang Ji-Guang
Published: January 2025

Objective

The objective of this study was to investigate the efficacy of the nitrendipine/atenolol combination in comparison with standard-dose nitrendipine or atenolol monotherapy in reducing blood pressure (BP) and blood pressure variability (BPV) as assessed by ambulatory BP monitoring.

Methods

In a randomized, crossover trial, 32 patients (30–65 years) with grade 1 hypertension and elevated daytime reading-to-reading BPV were randomly assigned to receive either the nitrendipine/atenolol combination (10/20 mg) or standard-dose nitrendipine (10 mg) or atenolol (25 mg) monotherapy for 6 weeks, followed by a crossover to another treatment for 6 weeks.

Results

The final analysis included 31 patients (mean [±SD] age, 49.2 ± 9.6 years) and 12 men. The nitrendipine/atenolol combination significantly reduced from baseline clinic and ambulatory BP and pulse rate (P ≤ 0.002), and 24 h and daytime systolic and diastolic BPV as assessed by SD and average real variability (P ≤ 0.042), but not the coefficient of variation nor nighttime BPV indices (P ≥ 0.06). Significant differences between the nitrendipine/atenolol combination and nitrendipine or atenolol monotherapy at the end of treatment were observed in clinic BP and pulse rate (P ≤ 0.042), but not in 24 h, daytime and nighttime blood pressure and pulse rate, except for daytime DBP and 24 h and daytime pulse rate (P ≤ 0.049). There were no significant differences in BPV between the combination and monotherpy groups at the end of treatment (P ≥ 0.25).

Conclusion

The nitrendipine/atenolol combination reduced daytime reading-to-reading BPV, but did not show superiority to nitrendipine or atenolol monotherapy.
Validation of the A&D BP UA-1100NFC/UA-1100NFC-W, hoseless upper arm-type home blood pressure devices, according to the ISO81060-2:2018/Amd 1:2020 protocol
Authors: Kario Kazuomi , Tomitani Naoko , Hoshide Satoshi
Published: January 2025

The aim of this study was to validate the performance of the A&D UA-1100NFC hoseless devices of two cuff sizes in monitoring blood pressure (BP) in the upper arm according to the International Organization for Standardization (ISO) 81060-2:2018/amendment (Amd) 1:2020 protocol. The accuracy of the UA-1100NFC (for arm circumferences of 22.0–32.0 cm) and the UA-1100NFC-W (for arm circumferences of 22.0–42.0 cm) was assessed using the same-arm sequence protocol as per the ISO 81060-2:2018/Amd 1:2020 standard. Individuals aged >12 years were recruited from the outpatients and volunteers of Jichi Medical University (Tochigi, Japan); 85 participants were included in the final analyses for each device. Both devices performed well against the standard; mean and SD values for the differences between the device-measured and observer-measured SBP and DBP values met both criterion 1 and criterion 2 of the standard [(UA-1100NFC) criterion 1: −3.71 ± 6.82 mmHg and 0.86 ± 6.33 mmHg, respectively; criterion 2: 5.65 mmHg and 5.87 mmHg, respectively; (UA-1100NFC-W) criterion 1: 0.73 ± 7.84 mmHg and 1.72 ± 6.44 mmHg, respectively; criterion 2: 6.49 mmHg and 5.86 mmHg, respectively]. The Bland–Altman plots did not show any systematic variation in the error. Both the UA-1100NFC and UA-1100NFC-W hoseless devices had a high level of accuracy and fulfilled the requirements of the ISO81060-2:2018/Amd 1:2020 validation standard. They are therefore suitable as home BP monitoring tools in patients with hypertension.
Feasibility of Pure Laparoscopic Donor Right Hepatectomy Compared to Open Donor Right Hepatectomy
Authors: Kim Sang-Hoon , Kim Ki-Hun , Yoon Young-In , Kang Woo-Hyoung , Lee Sang-Kyung , Hwang Shin , Ahn Chul-Soo , Moon Deok-Bog , Ha Tae-Yong , Song Gi-Won , Jung Dong-Hwan , Park Gil-Chun , Kim Ji Hoon , JWA EUN-KYOUNG , Na Byeong-Gon , Kim Sung Min , Oh Rak-Kyun , Jeong I-Ji , Ko Hyo Jung , Choi Minha , Won Dae Hyeon , KANG JI HOON , Lee Sung-Gyu
Published: January 2025

Objective:

This study aimed to compare morbidity of living donors and recipients after pure laparoscopic donor right hepatectomy (PLDRH) and open donor right hepatectomy (ODRH).

Background:

Donor and recipient morbidity have not been sufficiently reported in large-scale comparisons of PLDRH and ODRH.

Methods:

This retrospective study reviewed 3348 donors who underwent PLDRH (n=329) and ODRH (n=3019) and their corresponding recipients (n=3348) between January 2014 and August 2023. Donor complications and recipient biliary complications within 90 days were evaluated before and after 1:3 propensity score mathcing (PSM). Multivariate logistic regression analyses identified significant risk factors for donor major and biliary complications, as well as recipient bile leakage and biliary stricture.

Results:

For donors, PLDRH had fewer overall complications than ODRH (0.9% vs. 3.7%, P=0.009), with no significant differences in major (Clavien-Dindo III/IV) complications (P=0.057) and biliary complications (P=0.067), despite the absence of biliary complications in PLDRH. However, PLDRH showed longer warm ischemic time and operation time, and higher peak aspartate aminotransferase and alanine aminotransferase levels compared to ODRH in donors (P<0.001). These results remained consistent after PSM. Recipient biliary complications were comparable between PLDRH and ODRH, both before (P=0.806) and after PSM (P=0.149). Multiple portal veins were significant donor risk foctor for major (P=0.022), and biliary complications (P=0.001). Separated multiple bile ducts were common significant recipient risk factor for bile leakage (P=0.007) and biliary stricture (P=0.022)

Conclusions:

PLDRH could become the standard for donor right hepatectomy with careful consideration of portal and biliary variations for donor and recipient safety.
Pancreatic Fistula and Intraabdominal Fluid Collections after Distal Pancreatectomy
Authors: Pitakteerabundit Thakerng , Fagenholz Peter J. , Luckhurst Casey M. , Srinivas Rao Shravya , Kambadakone Avinash , Warshaw Andrew L. , Lillemoe Keith D. , Qadan Motaz , Fernandez-del Castillo Carlos
Published: January 2025

Objective:

To investigate the incidence and management of pancreatic fistula and fluid collections (FC) after distal pancreatectomy (DP).

Summary Background Data:

Pancreatic fistula and FC are common after DP. The relationship between pancreatic fistula, FC, and surgical drain placement remains unclear.

Methods:

We retrospectively reviewed patients who underwent DP at a single institution between June 2000 and August 2023.

Results:

1,212 patients were reviewed. Amongst them, 300 (24.9%) developed a biochemical leak, and 162 (13.4%) developed a postoperative pancreatic fistula (POPF). Of the 949 patients who had at least one postoperative cross-sectional imaging, 500 (52.7%) had a FC. Most FCs were asymptomatic (68%); however, when associated with POPF, the majority (n=121, 89%) became symptomatic and required treatment. Patients with POPF were significantly more likely to develop FC (OR 9.49), whereas biochemical leakage did not significantly increase this risk. Surgical drains did not significantly decrease the likelihood of FC (52% vs. 66%, P=0.06), but did increase POPF (13.9% vs. 4.7%, P<0.001) and the need for intervention for FC (33.6% vs. 12.9%, P=0.019).

Conclusions:

FC develop in over half of the patients undergoing DP, with approximately one-fourth of these cases associated with POPF. In most instances, FC remain asymptomatic; however, when linked to POPF, they are nine times more likely to become symptomatic and require therapeutic intervention. Although surgical drain placement may not contribute to FC, it was associated with a higher rate of POPF.
Improving sleep quality in maternity patients in a Singapore academic hospital: a best practice implementation project
Authors: Woo Tiffany Mei Ling , Lim Joanne Siew Hui , Begum Shafiqa , Goh Mien Li
Published: January 2025

Introduction:

Prolonged sleep deprivation and poor sleep quality are common complaints among pregnant and postpartum women, and they have adverse effects on the physiological and psychological well-being of mothers antenatally and postnatally.

Objectives:

The aim of this project was to improve antenatal and postnatal mothers’ night-time sleep quality during hospitalization in an obstetric ward through multi-faceted interventions.

Methods:

This project followed the JBI Model of Evidence-based Healthcare and applied the seven phases of the JBI Evidence Implementation Framework to conduct context analysis, strategy implementation, and review of practice using evidence-based audit criteria. JBI's Practical Application of Clinical Evidence System and the Getting Research into Practice situational analysis tool were used to support data collection and identify barriers and strategies. Mothers’ sleep quality was measured using an adapted St. Mary's Hospital Sleep Questionnaire.

Results:

Baseline audit results (0%) revealed that midwives and nurses were not implementing the multi-faceted interventions to promote sleep in mothers. The results in follow-up audit 1 and follow-up audit 2 achieved compliance of 63.3% (p < 0.000), respectively. Overall, the mothers were fairly satisfied with their sleep quality, were able to sleep longer, and felt more alert when waking up in the morning.

Conclusions:

There was an increase in compliance with best practices to improve mothers’ sleep quality in the obstetric wards, although these results could be further improved. Mothers’ perspectives of sleep promotion strategies should be explored in future projects to tailor the strategies to their needs. Sustainability plans include conducting follow-up audits and engaging ward nurses to continue implementing the multi-faceted interventions.

Spanish abstract:

http://links.lww.com/IJEBH/A307
Detection of Diffuse to Focal Myocardial Fibrosis by Cardiovascular Magnetic Resonance Against Histology in Mini-Swine
Authors: Zhang Huaying , Chen Cui , Yang Wenjing , Zhou Di , Wang Yining , Zhu Leyi , Jiang Mengdi , Zhang Qiang , Zhao Shihua , Piechnik Stefan K , Ferreira Vanessa M , Lu Minjie
Published: January 2025

Background

Myocardial fibrosis predicts adverse outcomes in myocardial infarction (MI) and other cardiovascular conditions. Cardiovascular magnetic resonance (CMR) can non-invasively detect focal and diffuse myocardial fibrosis, but comprehensive validation against histology remains scarce.

Aims

To assess the comparative diagnostic performance of CMR methods in detecting myocardial fibrosis, using a mini-swine model and histology as gold standard.

Methods

Eighteen mini-swine (16 MI; 2 healthy) underwent CMR cine, LGE, T1- and ECV-mapping. Two commonly-used T1-mapping methods – MOLLI 5(3)3 and ShMOLLI 5(1)1(1)1 – were included. Pathological sections were categorized as infarcted, peri-infarct, remote and healthy myocardium based on triphenyl tetrazolium chloride staining. Fibrotic burden was quantified by collagen volume fraction (CVF) into severe (CVF≥30%), moderate (CVF=10-25%), and mild (CVF=3-14%). The relationships between LGE, T1, ECV and CVF, and diagnostic performance using area-under-the-curve (AUC), were analyzed.

Results

For detecting severe fibrosis, LGE, T1 and ECV all had excellent diagnostic performance (AUC: LGE=0.93, ECVShMOLLI=0.96, T1ShMOLLI=0.91, T1MOLLI=0.93, ECVMOLLI=0.88). ECVShMOLLIshowed significantly better discriminatory accuracy than ECVMOLLIin detecting severe fibrosis and MI (both p<0.05), with the highest correlation to CVF (ECVShMOLLIr=0.86, ECVMOLLIr=0.82, T1ShMOLLIr=0.77, T1MOLLIr=0.77, semi-quantitative LGE r=0.75). Only T1ShMOLLIand ECVShMOLLI, but not LGE or T1MOLLI/ECVMOLLI, differentiated remote myocardium with mild fibrosis (CVF=8.23%) from healthy myocardium (CVF=2.01%).

Conclusions

CMR can detect severe to mild myocardial fibrosis as validated against histology. For low-grade fibrosis, T1-mapping significantly outperformed LGE. Choice of CMR methodologies matters for myocardial fibrosis detection, which has importance for clinical trial design.
Metabolic syndrome enhances SARS-CoV-2 disease severity and reduces mRNA vaccine efficacy in a mouse model
Authors: Geerling Elizabeth , Stone E. Taylor , Carpenter Danielle , Dickson Alexandria M. , Brien James D. , Pinto Amelia K.
Published: January 2025

Metabolic syndrome (MetS) is a cluster of pathophysiological conditions linked to the disruption of metabolic processes associated with energy storage and consumption. Approximately one-third of adults in the United States are currently diagnosed with MetS. Patients with MetS experience higher mortality rates following SARS-CoV-2 infection and exhibit poor vaccine efficacy following influenza virus vaccination compared to metabolically healthy individuals. However, the specific impact of MetS on immune responses to SARS-CoV-2 infection and vaccination has not been widely studied. To address this gap, we utilized high-fat diet feeding to establish a murine model of MetS, in which mice exhibit the same diagnostic criteria for MetS as human patients. We then used high-fat diet-induced MetS mice and regular chow diet-fed wild-type mice to analyze immune responses to SARS-CoV-2 infection and vaccination. Following SARS-CoV-2 infection, we monitored mice for disease severity, measured levels of virally induced inflammation, and quantified viral titers in various tissues. Our results indicate that MetS mice exhibit accelerated mortality post-infection, accompanied by elevated mRNA levels of inflammatory cytokine transcripts at sites of infection. Additionally, MetS alters the degree of viral replication across various tissues. Furthermore, our vaccination studies revealed that MetS reduces the potency of vaccine-induced neutralizing antibodies against both the ancestral SARS-CoV-2 strain and the Delta variant. Overall, our findings suggest that MetS exacerbates SARS-CoV-2 disease severity and diminishes vaccine efficacy, underscoring the need for tailored strategies to protect individuals with MetS from severe outcomes following infection and vaccination.

Impact

This study represents the first detailed account of the failure to generate protective neutralizing antibody responses to SARS-CoV-2 in mice with metabolic syndrome (MetS) following vaccination. The insights gained from this research inform future vaccine design and aid in identifying individuals at greater risk of breakthrough infections. By specifically isolating the risk associated with MetS, rather than obesity alone, these findings lay the groundwork for future investigations aimed at enhancing immune responses in individuals with MetS. This work is highly relevant to a broad audience, as it addresses a critical unmet need in vaccine development and provides essential guidance for the rational design of vaccines to protect vulnerable populations affected by MetS.
Run-and-tumble dynamics ofE. coliis governed by its mechanical properties
Authors: Wu-Zhang Bohan , Zhang Peixin , Baillou Renaud , Lindner Anke , Clément Eric , Gompper Gerhard , Fedosov Dmitry A.
Published: January 2025

The huge variety of microorganisms motivates fundamental studies of their behavior with a possibility to construct artificial mimics. A prominent example is theE. colibacterium which employs several helical flagella to exhibit a motility pattern that alternates between run (directional swimming) and tumble (change in swimming direction) phases. We establish a detailedE. colimodel, coupled to fluid flow described by the dissipative particle dynamics method, and investigate its run-and-tumble behavior. DifferentE. colicharacteristics, including body geometry, flagella bending rigidity, the number of flagella and their arrangement at the body are considered. Experiments are also performed to directly compare with the model. Interestingly, in both simulations and experiments, the swimming velocity is nearly independent of the number of flagella. The rigidity of a hook (the short part of a flagellum which connects it directly to the motor), polymorphic transformation (spontaneous change in flagella helicity) of flagella, and their arrangement at the body surface strongly influence the run-and-tumble behavior. Mesoscale hydrodynamics simulations with the developed model help us better understand physical mechanisms which governE. colidynamics, yielding the run-and-tumble behavior that compares well with experimental observations. This model can further be used to explore the behavior ofE. coliand other peritrichous bacteria in more complex realistic environments.
Mechanistic Insights into Sphingomyelin Nanoemulsions as Drug Delivery Systems for Non-Small Cell Lung Cancer Therapy
Authors: Docampo Emma Ramos , García-Fernández Jenifer , Mármol Inés , Morín-Jiménez Irene , Baleato María Iglesias , de la Fuente Freire María
Published: January 2025

Sphingomyelin Nanoemulsions (SNs) are promising drug delivery systems with potential for treating challenging tumors, including Non-Small Cell Lung Cancer (NSCLC), which has poor prognosis and a 5-year survival rate below 5%. Understanding the toxicity mechanisms and intracellular behavior of SNs is crucial for optimizing their therapeutic application. This study aims to investigate the interaction between SNs and A549 lung adenocarcinoma cells, focusing on their cytotoxic effects and mechanisms of cellular toxicity. SNs were synthesized and characterized for size, surface charge, and stability. A549 cells were treated with varying concentrations of SNs, and cellular uptake pathways were assessed using inhibitors of energy-dependent processes. Cytotoxicity was evaluated through an MTT assay to determine the IC50 value after 24 hours. Mechanisms of toxicity, including lysosomal and mitochondrial involvement, were examined using co-localization studies, mitochondrial membrane potential assays, and markers of apoptosis. SNs exhibited rapid cellular uptake via energy-dependent pathways. The IC50 concentration for A549 cells was 0.89 ± 0.15 mg/mL, suggesting favorable cytocompatibility compared to other nanocarriers. At IC50, SNs induced apoptosis characterized by lysosomal damage, mitochondrial membrane permeabilization, and release of apoptotic factors. These effects disrupted autophagic flux and contributed to cell death, demonstrating potential for overcoming drug resistance. Resveratrol-loaded SNs showed enhanced cytotoxicity, supporting their application as targeted drug delivery vehicles. This study highlights the potential of SNs as efficient drug delivery systems for NSCLC therapy, offering insights into their cellular interactions and toxicity mechanisms. These findings pave the way for the rational design of SN-based therapeutic platforms for cancer and other mitochondria-related diseases.
PLMFit : Benchmarking Transfer Learning with Protein Language Models for Protein Engineering
Authors: Bikias Thomas , Stamkopoulos Evangelos , Reddy Sai. T.
Published: January 2025

Protein language models (PLMs) have emerged as a useful resource for protein engineering applications. Transfer learning (TL) leverages pre-trained parameters to extract features to train machine learning models or adjust the weights of PLMs for novel tasks via fine-tuning through back-propagation. TL methods have shown potential for enhancing protein predictions performance when paired with PLMs, however there is a notable lack of comparative analyses that benchmark TL methods applied to state-of-the-art PLMs, identify optimal strategies for transferring knowledge and determine the most suitable approach for specific tasks. Here, we report PLMFit, a benchmarking study that combines, three state-of-the-art PLMs (ESM2, ProGen2, ProteinBert), with three TL methods (feature extraction, low-rank adaptation, bottleneck adapters) for five protein engineering datasets. We conducted over >3,150in silicoexperiments, altering PLM sizes and layers, TL hyperparameters and different training procedures. Our experiments reveal three key findings: (i) utilizing a partial fraction of PLM for TL does not detrimentally impact performance, (ii) the choice between feature extraction and fine-tuning is primarily dictated by the amount and diversity of data and (iii) fine-tuning is most effective when generalization is necessary and only limited data is available. We provide PLMFit as an open-source software package, serving as a valuable resource for the scientific community to facilitate the feature extraction and fine-tuning of PLMs for various applications.

ONE SENTENCE SUMMARY

PLMFit is a comparative analysis aimed at identifying the most effective strategies for transfer knowledge from protein language models by benchmarking fine-tuning techniques on a range of protein engineering tasks.
Myositis-specific autoantibodies recognizing Mi2 also target the autoimmune regulator (AIRE) protein at a shared PHD-zinc finger
Authors: Musai Jon , Jayaraman Sahana , Pak Katherine , Pinal-Fernandez Iago , Muñoz-Braceras Sandra , Casal-Dominguez Maria , Cho Eric , Fitisemanu Fa’alataitaua M. , Burbelo Peter D. , Kaplan Mariana J. , Warner Blake M. , Schiffenbauer Adam I. , Selva-O’Callaghan Albert , Milisenda José César , Rider Lisa G. , Benjamin Larman H. , Mammen Andrew L.
Published: January 2025

Objectives

In dermatomyositis patients with anti-Mi2 autoantibodies, autoantibodies can enter muscle cells, leading to the aberrant expression of genes normally repressed by the Mi2/nucleosome remodeling and deacetylation (NuRD) complex. However, the mechanism by which autoantibodies interfere with Mi2/NuRD function remains unclear. This study aimed to identify additional autoantibodies in anti-Mi2-positive patients as well as the specific epitopes recognized by anti-Mi2 and any novel autoantibodies.

Methods

Phage ImmunoPrecipitation Sequencing (PhIP-Seq) was used to screen serum samples from anti-Mi2-positive myositis patients for autoantibodies. Enzyme-linked immunosorbent assays (ELISA) and luciferase immunoprecipitation system (LIPS) immunoassays were used to detect autoantibodies in serum samples from myositis patients and healthy controls.

Results

PhIP-Seq identified autoantibodies recognizing the autoimmune regulator (AIRE) in sera from anti-Mi2 autoantibody-positive patients. Both anti-AIRE and anti-Mi2 autoantibodies predominantly recognized a homologous region of the plant homeodomain zinc finger type I (PHD1), which is critical for AIRE and Mi2/NuRD function. ELISA and LIPS testing showed that anti-Mi2 autoantibody-positive patients were positive for anti-AIRE autoantibodies, while AIRE reactivity was largely absent in healthy comparators, anti-Mi2 autoantibody-negative-myositis, and other autoimmune diseases. Affinity-purified anti-Mi2 autoantibodies recognized both Mi2 and AIRE by ELISA, whereas anti-Mi2-depleted immunoglobulin fractions did not recognize either protein.

Conclusions

Autoantibodies recognizing Mi2 also recognize AIRE at a homologous PHD1 finger. This region is required by the Mi2/NuRD complex to anchor the nucleosome and consequently repress gene expression. Our findings suggest that anti-Mi2 autoantibodies disrupt NuRD complex function by binding to the PHD1 domain. Further studies are needed to determine if anti-Mi2 autoantibodies bind other PHD1-containing proteins and their functional implications.
Stability of multi-species consortia during microbial metabolic evolution
Authors: Kehila Dan , Tafreshi Alireza G , Tokuriki Nobuhiko
Published: January 2025

Explaining multi-genic adaptations is a major objective of evolutionary theory. Metabolic pathways require multiple functional enzymes to generate a phenotype, and their evolution in microbes remains underexplored. In particular, sites polluted with manmade chemicals or “xenobiotics”, like plastic or pesticides, provide evidence for the rapid adaptation of novel metabolic pathways in microbes, which degrade these xenobiotics into utilizable nutrients. Decades of microbiological studies revealed that these pathways often are not consolidated within a single microbial species, but are rather distributed across several different ones, which cooperatively degrade xenobiotics. These species form remarkably stable consortia in the laboratory, but the determinants of this stability have not been hereto addressed. In this study, we show that trade-offs in microbial life history explain stable co-existence in a mathematical model of a three-species consortium, growing on a xenobiotic as the sole source of a limiting nutrient. Stability is predicted to hinge on a specific “ecological matching” between a species’ metabolic role in the novel metabolic pathway and its nutrient utilization strategy.
Glycan-reactive antibodies isolated from human HIV-1 vaccine trial participants show broad pathogen cross-reactivity
Authors: Jamieson Parker J. , Shen Xiaoying , Abu-Shmais Alexandra A. , Wasdin Perry T. , Janowska Katarzyna , Edwards Robert J. , Scapellato Garrett , Richardson Simone I. , Manamela Nelia P. , Liu Shuying , Barr Maggie , Gillespie Rebecca A. , Mimms Jessica , Suryadevara Naveenchandra , Sornberger Ty A. , Zost Seth , Parks Rob , Flaherty Shelby , Janke Alexis K. , Howard Bethany N. , Suresh Yukthi P. , Ruprecht Ruth M. , Crowe James E. , Carnahan Robert H. , Bailey Justin R. , Masaru Kanekiyo , Haynes Barton F. , Moore Penny L. , Acharya Priyamvada , Montefiori David C. , Kalams Spyros A. , Lu Shan , Georgiev Ivelin S.
Published: January 2025

HIV-1 continues to pose a significant global health challenge, requiring ongoing research into effective prevention and treatment strategies. Understanding the B cell repertoire that can be engaged upon vaccination in humans is crucial for the development of future preventive vaccines. In this study, PBMCs from HIV-negative participants in the multivalent HVTN124 human HIV-1 vaccine clinical trial were interrogated for HIV-reactive B cells using LIBRA-seq, a high-throughput B cell mapping technology. We report the discovery of glycan-reactive antibodies capable of neutralizing diverse heterologous HIV-1 virus strains. Further, isolated antibodies showed broad cross-reactivity against antigens from a variety of other pathogens, while remaining mostly negative on autoreactivity assays. The emerging class of glycan- reactive virus-neutralizing antibodies with exceptional breadth of pathogen cross- reactivity may present an effective target for vaccination at the population level.
TMPRSS2-ERGconfers resistance to antiandrogens: mechanism and therapeutic implications
Authors: Sekar Arunachalam , Chatterjee Rishita , Selvadurai Boobash Raj , Pal Lipika R. , Verma Aakanksha , Nataraj Nishanth Belugali , Garcia Diana Drago , Giri Suvendu , Genna Alessandro , Karatekin Feride , Gupta Nitin , Zerbib Mirie , Vinik Yaron , Avioz Tamir , Weizman Eviatar , David Eyal , Schaffer Alejändro A. , Pan Yunqian , Huang Haojie , van Weerden Wytske M. , Corey Eva , Hunt Hazel , Greenstein Andrew E. , Blecher-Gonen Ronnie , Oren Roni , Afek Ariel , Amit Ido , Lev Sima , Ku Anson , Kartal Sumeyra , Bright Jack R. , Lis Rosina T. , Dahut William L. , Sowalsky Adam G. , Ruppin Eytan , Yarden Yosef
Published: January 2025

Approximately 50% of prostate cancer (PCa) patients harbor fusions involving theTMPRSS2andERGgenes. Despite this, tailored therapies targeting the fused gene,tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed thattERGpromotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlightTMPRSS2-ERGas a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefittERG-positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
Genotype-specific roles of small extracellular vesicles in modulating metronidazole resistance inGiardia lamblia
Authors: Luna Pizarro Gabriel , Laiolo Jerónimo , Salas Nehuén , Patolsky Rocío G. , Díaz Pérez Luciano , Cotelo Camilo , Feliziani Constanza , Rópolo Andrea Silvana , Touz María Carolina
Published: January 2025

Giardia lamblia, a eukaryotic intestinal parasite, produces small extracellular vesicles (sEVs) as a conserved evolutionary mechanism. This study investigates the functional role of sEVs in transferring drug-resistance traits among parasites. sEVs derived from metronidazole (MTZ)-resistant clones are shown to modify the expression of enzymes involved in MTZ metabolism and the production of reactive oxygen species (ROS) in recipient wild-type parasites. These changes significantly alter the drug sensitivity of recipient parasites. The transfer efficiency and phenotypic impact vary depending on the genetic background of the isolates, highlighting a genotype-specific mechanism. Our findings reveal that sEVs act as mediators of phenotypic adaptation inG. lamblia, enhancing parasite survival under drug-induced stress. This study underscores the importance of sEVs in drug-resistance dynamics and provides a basis for exploring therapeutic interventions targeting EV-mediated resistance in giardiasis.

Highlights In brief

Small extracellular vesicles (sEVs) fromGiardia lambliamediate genotype-specific MTZ resistance transfer.

Small extracellular vesicles from drug-resistant clones (RsEVs) alter enzyme expression and reactive oxygen species (ROS) production in recipient trophozoites.

The genetic background ofG. lambliaisolates influences the effectiveness of resistance transfer.

Findings provide insights into resistance mechanisms and potential targets for new giardiasis therapies.
HPV integration in head and neck cancer: downstream splicing events and expression ratios linked with poor outcomes
Authors: Li Shiting , Xia Shaomiao , Lawas Maria , Kulshreshtha Aishani , Garb Bailey F. , Perera AA Chamila , Li Chen , Qin Tingting , Welch Joshua D. , D’Silva Nisha J. , Rozek Laura S. , Sartor Maureen A.
Published: January 2025

HPV integration (HPVint) is associated with carcinogenesis and tumor progression in HPV-associated cancers, including head and neck squamous cell carcinomas (HNSCC). While its impact on human DNA has been well characterized, its relationship with clinical outcomes remains unconfirmed. Here we investigate the consequences of HPVint both with respect to human and HPV characteristics by analyzing 261 HPV-associated HNSCC bulk and single-cell RNA-seq samples from five cohorts, and DNA HPVint events from 102 HPV+ participants in two of the cohorts. By leveraging this large meta-cohort, we first reveal an oncogenic network based on the recurrent HPV integration locations in HNSCC. We then classify HPVint-positive (HPVint(+)) participants by HPV RNA features, specifically based on spliced HPV-human fusion transcripts and ratios of HPV gene transcripts, showing that subsets of participants have worse clinical outcomes. Our analyses, focused mainly on RNA instead of DNA, expand our understanding of the carcinogenic mechanisms of HPVint, partially addressing the conflicting findings of whether HPVint is associated with aggressive phenotypes and worse clinical consequences, and provide potential biomarkers to advance precision oncology in HPV-associated HNSCC.
Multiple locomotion gaits in the mole cricket
Authors: Yuval Omer , Amir Avi , Ayali Amir
Published: January 2025

Insects are exceptionally robust walkers. Although different species exhibit distinct anatomical and functional specializations, they are also highly adaptive within these constraints. How such adaptations enable insects to efficiently navigate diverse environments and perform mechanical tasks remains far from fully explored. The mole cricket, which dwells underground, is one of the least studied insects, largely due to its cryptic lifestyle. It excels at digging tunnels and exhibits extreme morphological adaptations, particularly its exceptional fossorial forelegs. Its versatile locomotion, above and below ground, makes the mole cricket an attractive model system for studying the biomechanics of insect movement. Here we provide the first quantitative characterization of mole cricket locomotion. Using a tunnel-like arena, we recorded freely-moving insects and analyzed their various locomotion gaits. We identified and described three main modes of locomotion, including a backward-bound gait that has not previously been reported in any insect. To test specific hypotheses regarding form-function relationships and the generation of thrust, we integrated biomechanical modeling and deep reinforcement learning to simulate the observed gaits. Our work opens several future directions, from exploring context-dependent gait transitions to bio-inspired technological innovations.
Transcriptional and synaptic regulation of NMDA glutamate receptor-mediated hippocampal plasticity and memory
Authors: Parra-Damas Arnaldo , del Ser-Badia Anna , Fernandez-Olaya Xavier , Deprada-Fernandez Ángel , Enríquez-Barreto Lilian , Prius-Mengual José , Català-Solsona Judit , Brito Verónica , Rodríguez-Alvarez José , Ginés Silvia , Rodríguez-Moreno Antonio , Saura Carlos A.
Published: January 2025

Synapse-to-nucleus signaling regulates activity-dependent synaptic plasticity underlying memory by linking N-methyl-D-aspartate (NMDA) glutamate receptors (GluN) to gene transcription mediated by the transcription factor cAMP-response element binding protein (CREB), but the underlying gene programs mediating potentiation at excitatory synapses are unknown. Here, we analyzed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) datasets of mouse and human CREB and the synaptonuclear factor CREB-regulated transcription coactivator1 (CRTC1) to identify relevant target genes and biological pathways coupling neuronal activity to synaptic function/plasticity. Our analyses indicate that CRTC1 specifically couples neuronal activity with synaptic plasticity by binding to conserved promoters of CREB target genes comprising inducible transcription factors (includingc-fos,Crem,Npas4andNr4a1-3), and neuronal excitability and plasticity genes, includingNtrk2,Homer1,Dlg4(PSD-95) and the NMDA receptor subunitGrin1(GluN1). CRTC1/CREB target genes were highly enriched in gene ontology (GO) nuclear terms, including several members of the CREB family, and transcriptional modulators and repressors. Interestingly, GO enrichment and protein-protein interaction (PPI) network analyses revealed that genes mediating synapse-to-nucleus signaling (including most known synaptonuclear factors and direct interacting modulators) are collectively regulated by CREB/CRTC1, and that protein kinase C (PKC) is a key interactor of the CRTC1/14-3-3 complex at synapses. In agreement with thesein silicoanalyses, we show that CRTC1 regulates synaptic activity-dependent phosphorylation and synaptic recruitment of GluN1 mediated by PKC in hippocampal neurons, and that PKC activation reverses NMDA receptor-mediated currents and long-term potentiation (LTP) deficits caused by CRTC1 silencing in the hippocampus. Consistent with genomics and functional data, morphological and behavioral analyses show crucial roles of CRTC1 on dendritic spine structure, plasticity, and hippocampal-dependent associative memory. Our results support a model in which neuronal activity and synaptic inputs are integrated in the nucleus through conserved CREB/CRTC1-regulated transcriptional programs sustaining global synapse-to-nucleus signaling pathways impacting on synaptic plasticity and memory.
Lack of RNase HI affects virulence inSalmonella enterica
Authors: Jiménez-Espadafor Julia , Ortiz-Padilla Miriam , Pedraza-Delgado Diego A. , Bernal-Bayard Joaquín , Ramos-Morales Francisco , Balbontín Roberto
Published: January 2025

Bacterial virulence and antibiotic resistance are interconnected global threats that can synergize, multiplying their adverse effects on health and economy. Two proposed strategies to address this dual challenge are non-biocidal inhibition of virulence traits (anti-virulence strategy) and manipulation of eco-evolutionary dynamics in bacterial populations to hamper dissemination of antibiotic resistance (anti-resistance strategy). These strategies require to identify factors involved in bacterial gene expression, fitness and evolution. R-loops strongly influence these traits, as well as fitness of bacteria carrying antibiotic resistance mutation, making the enzyme responsible for R-loop degradation, the RNase HI, a promising target for anti-resistance approaches. Interestingly, the extensive involvement of R-loops in transcription initiation and termination could also make RNase HI a potential target for anti-virulence strategies. Here we explored this possibility by investigating the effects of RNase HI deficiency on traits associated with pathogenicity in the human pathogenSalmonella entericaserovar Typhimurium. We found that lack of RNase HI alters expression of virulence genes at population and single-cell levels, and bothex vivoand during infection of mammalian cells. Moreover, we showed that RNase HI depletion causes defects in phenotypes associated with virulence, such as motility, biofilm formation, and resistance to low pH. Coherently, we observed that the absence of RNase HI reducesSalmonella’s ability to survive within macrophages. Altogether, our results demonstrate the influence of R-loops on bacterial virulence, suggesting that RNase HI could serve as a target for anti-virulence strategies. This provides a theoretical framework for the development of dual anti-resistance and anti-virulence interventions based on RNase HI targeting.
The virulence regulatorbvgSis required for nutrient-induced filamentation inBordetella avium
Authors: Perslow Niklas G , Luallen Robert J
Published: January 2025

Bacteria can change morphology in response to stressors and changes in their environment, including infection of a host. We previously identified the bacterial species,Bordetella atropi, which uses nutrient-induced filamentation as a novel mechanism for cell-to-cell spreading in the intestinal epithelial cells of a nematode host. To further investigate the conservation of nutrient-induced filamentation in Bordetellae, we utilized the turkey-infecting speciesBordetella aviumwhich filaments in vitro when switched from a standard growth media to an enriched media. We conducted a selection-based filamentation screen withB. aviumand isolated two independent non-filamentous mutants that failed to filament in highly enriched media. These mutants contained different alleles inbvgS, the sensor in the two-component master virulence regulator (BvgAS) conserved across the Bordetella genus. To investigate the role ofbvgSin nutrient-induced filamentation, we conducted transcriptomics and found thatbvgSmutation resulted in loss of responsiveness to highly-enriched media, especially in genes related to nutrient uptake and metabolism. The most dysregulated gene in thebvgSmutant encoded for succinyl-CoA:acetate CoA-transferase (SCACT) and we were able to regulate filamentation with exogenous metabolites up and downstream of this enzyme. These data suggest thatbvgSregulates nutrient-induced filamentation by controlling metabolic capacity. Overall, we found that the virulence regulatorbvgSis required for nutrient-induced filamentation inB. avium, suggesting there may be conservation in Bordetellae for utilizing this morphological change as a virulence phenotype.
Unveiling the factors shaping innovation: a comparative analysis of emerging and advanced Asian economies
Authors: Pal Shreya , Mahalik Mantu Kumar , Mallick Hrushikesh
Published: January 2025

Purpose

This study examines the role of monetary and fiscal policies in shaping innovation for a balanced panel sample of seven emerging and five advanced Asian economies.

Design/methodology/approach

Using the Driscoll–Kraay estimator as a baseline technique and panel-corrected standard errors and kernel-based regularised least squares as robust methods, this study explores the factors that influence innovation in both emerging and advanced Asian economies from 1990 to 2021. Based on the Morgan Stanley Capital International categorisation, this study has used a sample of seven emerging and five advanced Asian nations to empirically understand the factors shaping innovation.

Findings

The findings indicate that broad money and economic growth have positive effects on innovation, whereas tax revenue, governance quality and economic globalisation indicate negative effects in emerging Asia. The findings further indicate that tax revenue, economic growth, governance quality and economic globalisation favour innovation in advanced Asia. The authors also find an adverse impact of broad money on total innovation in advanced Asia.

Originality/value

These findings are quite helpful for the stakeholders and policymakers looking for efficient and long-lasting innovation initiatives.