bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering of CD8
+
T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses
Authors: Meng Lina , Zhao Haichi , Chang Shangkun , Li Weiting , Tian Yinghui , Wang Ruihong , Wang Libian , Gu Tiejun , Wu Jiaxin , Yu Bin , Wang Chu , Yu Xianghui 
Published: February 2025

ABSTRACT

The application of immunotherapeutic strategies, such as chimeric antigen receptor-T cells and broadly neutralizing antibodies (bNAbs), for the treatment of human immunodeficiency virus (HIV) infection is hindered by the latent reservoirs and viral escape. Achieving long-term control of viral load in the absence of antiretroviral therapy requires a combination approach utilizing these immunotherapeutic strategies. For this purpose, we developed novel anti-HIV-1 synthetic Notch (synNotch) receptor-T cells, termed CD4-17b-VN, which express both a bNAb (VRC01) and a bispecific T cell-engaging protein (N6-αCD3) with antigenic control. The synNotch receptor-expressing cells can sense the viral antigen presented on both HIV-1 particles and the surface of target cells. A human T cell line equipped with the CD4-17b-VN circuit could effectively control VRC01 and N6-αCD3 secretion upon sensitization, suppress the infection of diverse subtypes of HIV-1 strains, and mediate specific bypass cytotoxic activity against infected and latency-reactivated cells. Additionally, CD4-17b-VN CD8
+
T cells exhibited long-lasting suppression of infected cells and stronger killing effect on latency-reactivated cells
in vitro
. Importantly, we demonstrated that the synNotch receptor did not increase susceptibility to HIV-1 infection in the engineered cells. Our study validates the concept of a synNotch platform-based T cell therapeutic approach that can deliver broadly therapeutic antibodies in an HIV-1 antigen-controlled manner, which may have important implications for the functional cure of AIDS.

IMPORTANCE

Adoptive transfer of effector T cells modified with a chimeric antigen receptor has been proposed as an applicable approach to treat human immunodeficiency virus (HIV) infection. The synNotch receptor (SNR) system serves as a versatile tool, enabling customized programming of input and output functions in mammalian cells. Herein, we report a novel synNotch platform-based approach for T cell engineering targeting both cell-free particles and infected cells by coupling antibody neutralization with cytotoxicity. Our findings demonstrate that the engineered CD4-17b SNR enables controllable production of functional anti-HIV-1 broadly neutralizing antibody and bispecific T cell-engaging protein upon recognition of the viral particle and cell surface antigens by the bifunctional synNotch-T cells. Human primary CD8
+
T cells equipped with the bifunctional synNotch circuit CD4-17b-VN can effectively suppress long-term viral replication and reduce latency-reactivated cells
in vitro
, without the undesired risk of being infected by the virus, suggesting their potential candidacy for AIDS therapy with prospects for future clinical applications.
Natural compounds target the M23B zinc metallopeptidase Mpg to modulate
Neisseria gonorrhoeae
Type IV pilus expression
Authors: Nicholson Kathleen R. , Yin Shaohui , Edwards Jennifer L. , Luan Chi-Hao , Seifert H Steven 
Published: February 2025

ABSTRACT

Neisseria gonorrhoeae
uses the Type IV pilus (T4p) to colonize several sites within humans by adhering to host cells and tissues. Previously, we identified a periplasmic M23B zinc metallopeptidase, Mpg, that is necessary to protect from oxidative and nonoxidative killing and these phenotypes are mediated by Mpg activities on T4p expression. Here, we use a high-throughput, target-based screening approach to identify novel inhibitors of Mpg’s enzymatic activity. We identified two natural compounds, punicalagin and chebulinic acid, which inhibit the peptidoglycan-hydrolyzing activity of Mpg in a dose-dependent manner. Moreover, treatment of
N. gonorrhoeae
with these compounds leads to a concomitant decrease in the number of T4p, similar to an
mpg
mutant. However, these compounds are not toxic to
N. gonorrhoeae
. These compounds exhibit activity against Mpg orthologs from other bacterial species. Notably, these natural compounds inhibit
N. gonorrhoeae
colonization and survival in cell culture models of infection. This work provides the characterization of two natural compounds with activity against
N. gonorrhoeae
T4p through the Mpg M23B class zinc metallopeptidase.

IMPORTANCE

Neisseria gonorrhoeae
is a global health burden with high transmission rates and multidrug resistance.
N. gonorrhoeae
encodes a Type IV pilus (T4p), which is a major colonization and virulence factor. The importance of the T4p in multiple stages of infection makes it an attractive drug target. Previously, we identified an M23B zinc metallopeptidase, Mpg, important for T4p production and T4p-mediated resistance to neutrophil killing. In this study, we identified two natural compounds, punicalagin and chebulinic acid, as novel inhibitors of Mpg’s enzymatic activity that thus inhibit T4p expression. These findings identify two potential anti-colonization and anti-virulence compounds and provide a framework to target T4p components for future screens, poising the field to potentially discover additional compounds to combat
N. gonorrhoeae
infection.
A novel function of short cationic peptide FP-CATH9 without antimicrobial activity reverses resistance to minocycline in common multidrug-resistant gram-negative bacteria
Authors: Tang Yingqi , Liu Jiye , Yan Jiani , Xie Zhixiong , Zhong Lipeng 
Published: February 2025

ABSTRACT

The increase in bacterial resistance to minocycline and other tetracyclines poses a serious threat to global public health. Because the development of new antibiotics has proven problematic, antibiotic sensitization therapy is now an effective coping strategy. While antimicrobial peptides generally exhibit broad-spectrum antibacterial activity and good biocompatibility, naturally truncated portions of antimicrobial peptides (such as snake cathelicidin) often do not exhibit antimicrobial activity, and their function remains unknown. FP-CATH9 is a short cationic peptide derived from FP-CATH (snake cathelicidin antimicrobial peptide) with an amphiphilic α-helical structure and no discernible antibacterial activity. However, FP-CATH9 was previously found to significantly enhance the activity of minocycline against gram-negative bacteria. In the present paper, clinically relevant minocycline-resistant gram-negative bacteria (
Escherichia coli
,
Klebsiella pneumoniae
,
Acinetobacter baumannii
, and
Pseudomonas aeruginosa
) were used as test bacteria for antibiotic sensitization screening. The sensitization activity of FP-CATH9 was found to be dose dependent in a double-dilution assay. The synergistic activity of FP-CATH9 on minocycline was subsequently determined using the checkerboard method. An ethidium bromide efflux test revealed that FP-CATH9 caused an accumulation of minocycline in bacteria. Additionally, FP-CATH9 exhibited low hemolytic activity on red blood cells and low cytotoxicity on Raw264.7 cells. In an
in vivo
model of bacterial infection, FP-CATH9 combined with minocycline exhibited an 80% protective effect on
Galleria mellonella
larvae infected with multidrug-resistant
K. pneumoniae
. In summary, FP-CATH9 is a new antibiotic adjuvant that reverses the resistance of gram-negative bacteria to minocycline by increasing intracellular accumulation of minocycline. This finding has broad application potential.

IMPORTANCE
The existence of the efflux pump system enables bacteria to expel antibiotics, reduce the concentration of antibiotics in cells, and make antibiotics unable to effectively inhibit or kill bacteria, which is one of the main mechanisms of bacterial resistance to antibiotics. However, some efflux pumps are substrate specific, while others are with a wide range of substrates. In this study, FP-CATH9 as a new antibiotic adjuvant can specifically reverse the resistance of gram-negative bacteria to minocycline by increasing the intracellular accumulation of minocycline in bacteria and provides a new way to solve the increasing problem of bacterial drug resistance.
Supplemental Material: Tracking a common mantle source: From southwest Iberia to the Madeira-Canarias Islands
Authors: Pereira Ricardo , al. et 
Published: February 2025

<p>(1) Detailed methodology used in this work; (2) a summary table with the magmatic occurrences within the Central-East Atlantic Alkaline Province, showing the geochronological data used in this work, along with its references; (3) supplemental figures that show the different paleogeographic reconstructions; and (4) a video showing the tectonic plates moving over a fixed mantle upwelling, from which the multiple magmatic manifestations were derived. </p>
A Study of the Influence of Packaging Material on the Development of a Pattern in Semi-hard Cheeses Produced Using Propionic Acid Bacteria
Authors: Rogov G. N. , Smirnova T. S. , Kartashov S. I. , Kovalishina D. A. , Kalmykova M. V. , Namsaraev Z. B. 
Published: February 2025

Abstract
Propionic acid bacteria play an important role in the formation of a pattern on cheese produced using them. In recent years, cheese producers have actively used the rindless technology for its ripening, which has made it difficult to obtain a pre-defined cheese pattern. The influence of the type of packaging material, the ripening temperature in the main chamber, and the salting technology on the process of pattern formation in semi-hard cheese with the involvement of propionic acid bacteria has been studied. The pattern in cheese was analyzed using the non-destructive method of magnetic resonance imaging. Our studies have shown that, the pattern formation during the production of semi-hard cheeses using propionic acid bacteria weighing 5–7 kg and a mass moisture fraction of 44–45% depends on the gas permeability of the polymer material used for cheese ripening and on the temperature in the main ripening chamber. The lowest amount of gas was formed when using a polymer material with a carbon dioxide permeability of 50 cm3/(m2 day). The best result was observed when cheese was ripened in packages with CO2 permeability above 1750 cm3/(m2 day) at a temperature of 24°C in the main ripening chamber. The lowering of the temperature in the main chamber to 18°C reduces the volume of formed gas by 5 times. It has also been established that the decrease in the permeability of the polymer material for carbon dioxide from 1750 to 750 cm3/(m2 day) has little effect on the development of a pattern in cheese. Increasing the salt concentration gradient in the surface layer of cheese reduces the volume of eyes formed in the subrind layer, thereby reducing the potential for defects in the finished product.
Metastatic breast cancer diagnosed on upper gastrointestinal endoscopy
Authors: LIM Annabelle Xiao Hui , Ellis-Owen Rwth , Morgan Meleri , Abdalla Badr 
Published: February 2025

A woman in her late 60s was referred with a positive faecal immunochemical test and change in bowel habit; a suspicion of gastrointestinal (GI) cancer led to straight-to-test vetting for colonoscopy, which was unsuccessful due to a nontraversable, fixed sigmoid colon, secondary to prior hysterectomy and adhesions.Radiological evaluation with CT scanning revealed an abnormally thickened stomach, with subsequent upper GI endoscopy and biopsy findings confirming the presence of invasive poorly differentiated carcinoma consistent with metastatic invasive lobular carcinoma originating from the breast. Immunohistochemistry testing for gross cystic disease fluid protein was positive, and the tumour demonstrated positive oestrogen receptor status, while human epidermal growth factor receptor 2 status was negative. The immunohistochemical profile of this carcinoma was identical to that observed in synchronous breast cores, indicating metastatic invasive lobular carcinoma of the breast.This unusual presentation of breast cancer metastasis is not well recognised.
Integrative anticoagulation of nafamostat mesylate in double plasma molecular adsorption system plus sequential half-dose plasmapheresis for patients with liver failure: a randomised controlled trial protocol
Authors: Sun Xiankun , Wang Fang , Chen Zhiwen , Liao Juan , Yang Yingying , Bai Lang , Zhang Ling 
Published: February 2025

IntroductionNafamostat mesylate (NM) is widely recognised as a premier anticoagulant, especially in Japan and Korea. However, it has not yet been used as an anticoagulant in double plasma molecular adsorption system (DPMAS) plus sequential half-dose plasmapheresis (PE) therapy. This study aims to comprehensively evaluate the safety and efficacy of NM-integrated anticoagulation during DPMAS plus sequential half-dose PE therapy for patients with liver failure.Methods and analysisA two-arm, open-label, parallel, randomised controlled trial involving 132 patients with liver failure will be conducted in China. Eligible participants will be randomly allocated to either the nafamostat mesylate integrative anticoagulation group or the heparin integrative anticoagulation group, employing a central randomisation system at a 1:1 ratio throughout the course of DPMAS plus sequential half-dose PE therapy. The primary outcome includes the number of successfully completed DPMAS plus sequential half-dose PE therapy. The secondary outcomes include liver function indicators, extracorporeal circulation pressures, coagulation function parameters, all-cause mortality rates and survival rates. Clinical safety will be assessed by analysis of the number of bleeding events, the number of clotting events and adverse events. Outcome analyses will be performed on both the intention-to-treat population, which includes all patients randomised, and the per-protocol population, which includes eligible patients who adhere to the planned treatment and follow-ups.Ethics and disseminationThe trial protocol was approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (approval number (2022)860). During the protocol revision process, all changes were reexamined and reapproved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University. The results will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberChiCTR2200064725.
Non-malignant gynaecological disease and risk of cardiovascular or cerebrovascular disease: a systematic review and meta-analysis
Authors: Colombo Giorgia Elisabeth , Mahamat-Saleh Yahya , Armour Mike , Madan Kedar , Sabag Angelo , Kvaskoff Marina , Missmer Stacey A , Condous George , Pathan Faraz , Leonardi Mathew 
Published: February 2025

BackgroundCardiovascular disease is the leading cause of death globally. Non-malignant gynaecological diseases (NMGD) significantly affect patient health and well-being and may be associated with cardiovascular or cerebrovascular disease (C/CVD).MethodsSeven databases were searched for relevant studies up to 21 April 2024. Observational studies reporting risk estimates and 95% CIs for the association between NMGD and C/CVD were included. Data were extracted by two independent reviewers. Random effects models were used to calculate summary relative risk (SRR) with 95% CI. Composite C/CVD outcome was defined as a combination of ischaemic heart disease, cerebrovascular disease, heart failure, and peripheral vascular disease. The ROBINS-I tool defined study quality and risk of bias.ResultsWe screened 6639 studies, of which 59 were eligible for full-text review and 28 were included in our analysis, comprising a total of 3 271 242 individuals. The majority (53.5%) of the studies were scored as having a ‘serious’/‘critical’ risk of bias. Overall, individuals with an NMGD had a significantly greater risk of composite C/CVD with low heterogeneity among contributing studies (SRR 1.28, 95% CI 1.20 to 1.37; n=16 studies, I2=65.3%), ischaemic heart disease (SRR 1.41, 95% CI 1.31 to 1.51; n=21 studies, I2=73.7%), and cerebrovascular disease (SRR 1.33, 95% CI 1.18 to 1.51; n=16 studies, I2=91.5%). In NMGD-specific analyses, the risk of C/CVD and its components was greater among those with a history of endometriosis or polycystic ovary syndrome.ConclusionsWe found an overall association between NMGD and C/CVD across all studies. However, estimates from individual studies varied substantially.
Developing and testing the predictive validity of household firearm storage measures: insights from rural Alaska
Authors: Sokol Rebeccah , Mueller-Williams Amelia , Porter Kelsey , Leys Megan , Apala Flaherty Aneliese , Wexler Lisa 
Published: February 2025

IntroductionMeasuring change in firearm storage is paramount to evaluating if interventions influence storage. Yet, there is little empirical basis for how to measure this change. This methodology study compared three different firearm storage measures using data from the Family Safety Net trial (n=46), a randomised controlled trial among firearm-owning adults in a rural Alaska Native community to encourage unloaded and locked firearm storage.MethodsThe team compared baseline and 1-month follow-up measures of household firearm storage: (1) cumulative firearm accessibility, (2) average firearm accessibility, and (3) number of unlocked firearms. All measures included information about locking status; the cumulative and average firearm accessibility measures incorporated additional information about ammunition. Unadjusted and adjusted generalised estimating equations evaluated the associations of the storage measures with adult perceptions of youth firearm access. Receiver operating characteristic curves from unadjusted models compared the measures’ abilities to predict adult perceptions of youth firearm access.ResultsAll household firearm storage measures were sensitive to change between baseline and 1 month follow-up (ps<0.05). These measures demonstrated a similar and moderate ability to predict adult perceptions of youth access (area under the curve range: 0.68–0.76).ConclusionThe number of unlocked firearms is an easily interpretable outcome when evaluating the effect of firearm storage interventions on storage practices, and it performed similarly well in predicting adults’ perceptions of youth firearm access as compared with more complex measures. Research that evaluates the ability of firearm storage measures to predict actual youth access will inform interventions to prevent youth firearm access.
Do scoring systems help us to estimate prognosis after mechanical thrombectomy? Data from the German Stroke Registry
Authors: Hahn Marianne , Gröschel Sonja , Paul Roman , Weitbrecht Luis , Protopapa Maria , Reder Sebastian , Othman Ahmed E , Gröschel Klaus , Uphaus Timo 
Published: February 2025

BackgroundNumerous scoring systems have been developed to individualize estimation of functional outcome after endovascular thrombectomy (EVT) of acute ischemic stroke. The aim of our study was to assess their utility for clinical practice based on a large cohort from real-world care of EVT.MethodsFor 13 082 patients included in the German Stroke Registry Endovascular Treatment (GSR-ET) (July 2015 to December 2021), we calculated the following prognostic tools: pre-interventional PRE-, Totaled Health Risks in Vascular Events – Endovascular therapy (THRIVE-EVT)- and Computed Tomography for Late Endovascular Reperfusion (CLEAR) scores and post-interventional MR PREDICTS@24 hours and BET-score. Area under the receiver operating characteristic curve (AUC) analyses in the total cohort and pre-defined subgroups were performed to determine each tool’s prognostic value for good functional outcome (modified Rankin Scale (mRS) 0–2) and mortality at 90-day follow-up.ResultsAll pre-interventional tools achieved a moderate prognostic value for predicting good functional outcome (PRE: AUC (95% confidence interval): 0.757 (0.747–0.768), THRIVE-EVT: 0.751 (0.740–0.761), CLEAR: 0.731 (0.72–0.742)), had a higher predictive value than the admission National Institute of Health Stroke Scale ((NIHSS); 0.705 (0.694–0.716), all P<0.001), but were inferior to the NIHSS 24 hours after EVT (0.864 (0.855–0.872), all P<0.001). Predictive capacity for mortality was less accurate (AUC range: 0.697–0.729). Subgroup analyses revealed that the PRE-score was most robust at predicting good functional outcome, whereas the THRIVE-EVT score was superior in predicting mortality. Post-interventionally, MR PREDICTS@24 hours yielded high predictive accuracy for good functional outcome and mortality (both AUC >0.85), superior to 24-hour NIHSS for all subgroups, except patients <50 years of age.ConclusionPre-interventional scoring tools predict functional outcome after EVT better than stroke severity alone. Post-interventionally, the MR PREDICTS@24 hours tool adds predictive value to the 24-hour NIHSS as a single prognostic feature. Multivariate prognostic tools incorporating (post-)procedural information enable individualization of prognosis assessment after EVT under routine-care conditions.
Safety and efficacy of tirofiban versus traditionaldualantiplatelettherapy in endovasculartreatment of intracranialaneurysms: asystematicreview and meta-analysis
Authors: Xiao ZhenKun , Hu XuYi , Deng LiangJie , Liu JianHua , Liu Aihua 
Published: February 2025

BackgroundThe selection of antiplatelet agents plays a crucial role in ensuring the safety and efficacy of endovascular treatment for intracranial aneurysms (IA). Currently, the primary agents used include tirofiban and traditional dual antiplatelet therapy (DAPT). Due to the lack of high-level consolidated evidence in this field, we conducted the first systematic review and meta-analysis aimed at comparing the safety and efficacy of tirofiban vs traditional DAPT in the endovascular treatment of IA.MethodsStudies published before November 1, 2024, were searched in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials. The primary outcome was thrombosis, and secondary outcomes included intracranial hemorrhage (ICH), non-intracranial bleeding events (NoICH-BE), ischemic stroke (IS), and follow-up prognosis. Relative risks (RRs) were synthesized for comparison between tirofiban and DAPT groups.ResultsNine studies involving 2481 patients were included. Tirofiban significantly reduced the risk of thrombosis compared with DAPT (RR, 0.292; 95% CI, 0.174 to 0.492; P<0.001). It did not increase risks of ICH (RR, 0.633; P=0.125), NoICH-BE (RR, 0.253; P=0.259), IS (RR, 0.730; P=0.172), or poor prognosis (RR, 0.981; P=0.896).ConclusionTirofiban effectively lowers the risk of thrombosis without increasing bleeding or adverse prognosis risks compared with DAPT. It shows promise as an alternative antiplatelet therapy for IA treatment, but further large-scale studies are needed to confirm these findings.