bluuebunny/crossref_metadata_2025 huggingface dataset:
Mediation Effect of Work Stress on the Relationship between Role Conflict, Role Ambiguity, and Employees Performance
Authors: Wahjoedi Tri
Published: December 2023

Purpose – The aim of this study was to examine how role conflict and role ambiguity, mediated by work stress, influenced employees performance. 
Methodology – A quantitative analysis was performed by using the Slovin formula for a total sample of 114 employees from PT MSP, a prominent household appliances company in East Java, Indonesia. The collected data were analyzed using SEM SmartPls-3.
Results – The results showed that both role conflict and role ambiguity exerted a significant negative impact on employees performance, and also contributed to increased work stress. Moreover, work stress showed a significant negative impact on employees performance. The inclusion of work stress as an intermediary highlighted its role in mediating the negative relationship between role conflict, role ambiguity, and employees performance.
Originality – Incorporating work stress as a mediator in the connection between these variables enriched the exploration of the interrelation. This intricate relationship required a deeper understanding for the optimization of employees performance.
Magnetically‐actuated microcages for cells entrapment, fabricated by laser direct writing via two photon polymerization
Authors: Popescu Roxana Cristina , Calin Bogdan Stefanita , Tanasa Eugenia , Vasile Eugeniu , Mihailescu Mona , Paun Irina Alexandra
Published: December 2023

The manipulation of biological materials at cellular level constitutes a sine qua non and provocative research area regarding the development of micro/nano‐medicine. In this study, we report on 3D superparamagnetic microcage‐like structures that, in conjunction with an externally applied static magnetic field, were highly efficient in entrapping cells. The microcage‐like structures were fabricated using Laser Direct Writing via Two‐Photon Polymerization (LDW via TPP) of IP‐L780 biocompatible photopolymer/iron oxide superparamagnetic nanoparticles (MNPs) composite. The unique properties of LDW via TPP technique enabled the reproduction of the complex architecture of the 3D structures, with a very high accuracy i.e., about 90 nm lateral resolution. 3D hyperspectral microscopy was employed to investigate the structural and compositional characteristics of the microcage‐like structures. Scanning Electron Microscopy coupled with Energy Dispersive X‐Ray Spectroscopy was used to prove the unique features regarding the morphology and the functionality of the 3D structures seeded with MG‐63 osteoblast‐like cells. Comparative studies were made on microcage‐like structures made of IP‐L780 photopolymer alone (i.e., without superparamagnetic properties). We found that the cell‐seeded structures made by IP‐L780/MNPs composite actuated by static magnetic fields of 1.3 T were 13.66 ± 5.11 folds (p < 0.01) more efficient in terms of cells entrapment than the structures made by IP‐L780 photopolymer alone (i.e., that could not be actuated magnetically). The unique 3D architecture of the microcage‐like superparamagnetic structures and their actuation by external static magnetic fields acted in synergy for entrapping osteoblast‐like cells, showing a significant potential for bone tissue engineering applications.
A time-resolved fluorescence microsphere-lateral flow immunochromatographic strip for quantitative detection of Pregnanediol-3-glucuronide in urine samples
Authors: Lin Jiasheng , Li Sanhua , Ye Benchen , Zheng Weigang , Wang Huihui , Liu Ying , Wang Dong , Wu Zaihui , Dong Wen-Fei , Zan Minghui
Published: December 2023

Introduction: Pregnanediol-3-glucuronide (PdG), as the main metabolite of progesterone in urine, plays a significant role in the prediction of ovulation, threatened abortion, and menstrual cycle maintenance.

Methods: To achieve a rapid and sensitive assay, we have designed a competitive model-based time-resolved fluorescence microsphere-lateral flow immunochromatography (TRFM-LFIA) strip.

Results: The optimized TRFM-LFIA strip exhibited a wonderful response to PdG over the range of 30–2,000 ng/mL, the corresponding limit of detection (LOD) was calculated as low as 8.39 ng/mL. More importantly, the TRFM-LFIA strip was innovatively used for the quantitative detection of PdG in urine sample, and excellent recovery results were also obtained, ranging from 97.39% to 112.64%.

Discussion: The TRFMLFIA strip possessed robust sensitivity and selectivity in the determination of PdG, indicating the great potential of being powerful tools in the biomedical and diagnosis region.
Synergistic potential of teriflunomide with fluconazole against resistant Candida albicans in vitro and in vivo
Authors: Li Xiuyun , Kong Bing , Sun Yaqiong , Sun Fenghua , Yang Huijun , Zheng Shicun
Published: December 2023

Introduction

Candida albicans is the primary cause of systemic candidiasis, which is involved in high morbidity and mortality. Drug resistance exacerbates these problems. In addition, there are limited antifungal drugs available. In order to solve these problems, combination therapy has aroused great interest. Teriflunomide is an immunosuppressant. In the present work, we aimed to identify whether teriflunomide can reverse the resistance of Candida albicans in the presence of sub-inhibitory concentrations of fluconazole in vitro and in vivo.

Methods

Seven Candida albicans isolates were used in this study. Susceptibility of Candida albicans in vitro to the drugs was determined using a checkerboard microdilution assay in accordance with the recommendations of the Clinical and Laboratory Standards Institute. The effects of drugs on biofilm biomass of Candida albicans were determined by crystal violet staining. The development ability of Candida albicans hyphae was performed using a modified broth microdilution method. Galleria mellonella was used for testing the in vivo efficacy of the combination therapies.

Results

We found that the combination of teriflunomide (64 µg/mL) and fluconazole (0.5-1 µg/mL) has a significant synergistic effect in all resistant Candida albicans isolates (n=4). Also, this drug combination could inhibit the immature biofilm biomass and hyphae formation of resistant Candida albicans. Galleria mellonella was used for testing the in vivo efficacy of this combination therapies. As for the Galleria mellonella larvae infected by resistant Candida albicans, teriflunomide (1.6 µg/larvae) combined with fluconazole (1.6 µg/larvae) significantly increased their survival rates, and reduced the fungal burden, as well as damage of tissue in comparison to that in the control group or drug monotherapy group.

Conclusion

These results expand our knowledge about the antifungal potential of teriflunomide as an adjuvant of existing antifungal drugs, and also open new perspectives in the treatment of resistant Candida albicans based on repurposing clinically available nonantifungal drugs.
Case Report: Four cases of cardiac sarcoidosis in patients with inherited cardiomyopathy—a phenotypic overlap, co-existence of two rare cardiomyopathies or a second-hit disease
Authors: Ebbinghaus Hans , Ueberham Laura , Husser-Bollmann Daniela , Bollmann Andreas , Paetsch Ingo , Jahnke Cosima , Laufs Ulrich , Dinov Borislav
Published: December 2023

Cardiac sarcoidosis (CS), a rare condition characterized by non-caseating granulomas, can manifest with symptoms such as atrioventricular block and ventricular tachycardia (VT), as well as mimic inherited cardiomyopathies. A 48-year-old male presented with recurrent VT. The initial 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan showed uptake of the mediastinal lymph node. Cardiovascular magnetic resonance (CMR) demonstrated intramyocardial fibrosis. The follow-up 18FDG-PET scan revealed the presence of tracer uptake in the left ventricular (LV) septum, suggesting the likelihood of CS. Genetic testing identified a pathogenic LMNA variant. A 47-year-old female presented with complaints of palpitations and syncope. An Ajmaline provocation test confirmed Brugada syndrome (BrS). CMR revealed signs of cardiac inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of cardiac sarcoidosis. Polymorphic VT was induced during an electrophysiological study, and an implantable cardioverter-defibrillator (ICD) was implanted. A 58-year-old woman presented with sustained VT with a prior diagnosis of hypertrophic cardiomyopathy (HCM). A genetic work-up identified the presence of a heterozygous MYBC3 variant of unknown significance (VUS). CMR revealed late gadolinium enhancement (LGE), while the 18FDG-PET scan demonstrated LV tracer uptake. The immunosuppressive therapy was adjusted, and no further VTs were observed. A 28-year-old male athlete with right ventricular dilatation and syncope experienced a cardiac arrest during training. Genetic testing identified a pathogenic mutation in PKP2. The autopsy has confirmed the presence of ACM and a distinctive extracardiac sarcoidosis. Cardiac sarcoidosis and inherited cardiomyopathies may interact in several different ways, altering the clinical presentation. Overlapping pathologies are frequently overlooked. Delayed or incomplete diagnosis risks inadequate treatment. Thus, genetic testing and endomyocardial biopsies should be recommended to obtain a clear diagnosis.
Mechanism of carbonate assimilation by intraplate basaltic magma and liquid immiscibility: example of Wangtian’e volcano (Changbaishan volcanic area, NE China)
Authors: Andreeva Olga A. , Dubinina Elena , Andreeva Irina A. , Yarmolyuk Vladimir V. , Bychkov Andrey , Borisova Anastassia , Ji Jianqing , Zhou Xin , Kovalchuk Elena V. , Borisovsky Sergey Y. , Averin Alexey A.
Published: December 2023

The balance of CO2 during abundant basaltic magma production is an important factor of volcanic hazards and climate. In particular, this can be explored based on CO2-rich mantle-derived magmas or carbonate assimilation by basaltic melts. To reconstruct the origin of Fe-rich carbonates hosted by Cenozoic basalts from Wangtian’e volcano (northeast China), we studied elemental compositions of melt, crystalline and fluid inclusions in magmatic minerals as well as the oxygen and carbon isotope compositions of the plagioclase and carbonates from basalts. The crystallization of basaltic magmas occurred in shallow chamber (∼4 km) at temperatures of 1,180°C–1,200°C and a pressure of 0.1 ± 0.01 GPa. Stable Fe-rich carbonates occur in the Wangtian’e tholeiite basalts as groundmass minerals, crystalline inclusions in plagioclase and globules in melt inclusions, which suggests that they crystallized from a ferrocarbonate melt. The values of δ18О and δ13С in the minerals analyzed by laser fluorination method are in line with the sedimentary source of Fe-rich carbonates, indicating assimilation and partial decomposition of carbonate phases. The parent ferrocarbonate melt could be produced during interactions between the basaltic magma and the crustal marbles. The phase diagram and thermodynamic calculations show that the ferrocarbonate melt is stable at a temperature of 1,200°C and a pressure of 0.1 GPa. Our thermodynamic calculations show that carbonate melt containing 73 wt% FeCO3, 24 wt% MgCO3 and 3 wt% CaCO3 is in thermodynamic equilibrium with silicate melt in agreement with our natural observations. The proposed mechanism is crustal carbonate sediment assimilation by the intraplate basaltic magma resulting in the melt immiscibility, production of the ferrocarbonate melt and the following Fe-rich carbonate mineral crystallization during magma residence and cooling.
Mendelian randomization indicates causal effects of estradiol levels on kidney function in males
Authors: Nasr M. Kamal , Schurmann Claudia , Böttinger Erwin P. , Teumer Alexander
Published: December 2023

Context

Chronic kidney disease (CKD) is a public health burden worldwide. Epidemiological studies observed an association between sex hormones, including estradiol, and kidney function.

Objective

We conducted a Mendelian randomization (MR) study to assess a possible causal effect of estradiol levels on kidney function in males and females.

Design

We performed a bidirectional two-sample MR using published genetic associations of serum levels of estradiol in men (n = 206,927) and women (n = 229,966), and of kidney traits represented by estimated glomerular filtration rate (eGFR, n = 567,460), urine albumin-to-creatinine ratio (UACR, n = 547,361), and CKD (n = 41,395 cases and n = 439,303 controls) using data obtained from the CKDGen Consortium. Additionally, we conducted a genome-wide association study using UK Biobank cohort study data (n = 11,798 men and n = 6,835 women) to identify novel genetic associations with levels of estradiol, and then used these variants as instruments in a one-sample MR.

Results

The two-sample MR indicated that genetically predicted estradiol levels are significantly associated with eGFR in men (beta = 0.077; p = 5.2E-05). We identified a single locus at chromosome 14 associated with estradiol levels in men being significant in the one-sample MR on eGFR (beta = 0.199; p = 0.017). We revealed significant results with eGFR in postmenopausal women and with UACR in premenopausal women, which did not reach statistical significance in the sensitivity MR analyses. No causal effect of eGFR or UACR on estradiol levels was found.

Conclusions

We conclude that serum estradiol levels may have a causal effect on kidney function. Our MR results provide starting points for studies to develop therapeutic strategies to reduce kidney disease.
Exploring the implications of blocking renin-angiotensin-aldosterone system and fibroblast growth factor 23 in early left ventricular hypertrophy without chronic kidney disease
Authors: Watanabe Kentaro , Fujii Hideki , Okamoto Kohei , Kono Keiji , Goto Shunsuke , Nishi Shinichi
Published: December 2023

Background

Whether fibroblast growth factor 23 (FGF23) directly induces left ventricular hypertrophy (LVH) remains controversial. Recent studies showed an association between FGF23 and the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to investigate changes in FGF23 levels and RAAS parameters and their influences on LVH.

Methods

In the first experiment, male C57BL/6J mice were divided into sham and transverse aortic constriction (TAC) groups. The TAC group underwent TAC at 8 weeks of age. At 1, 2, 3, and 4 weeks after TAC, the mice were sacrificed, and blood and urine samples were obtained. Cardiac expressions of FGF23 and RAAS-related factors were evaluated, and cardiac histological analyses were performed. In the second experiment, the sham and TAC groups were treated with vehicle, angiotensin-converting enzyme (ACE) inhibitor, or FGF receptor 4 (FGFR4) inhibitor and then evaluated in the same way as in the first experiment.

Results

In the early stage of LVH without chronic kidney disease, serum FGF23 levels did not change but cardiac FGF23 expression significantly increased along with LVH progression. Moreover, serum aldosterone and cardiac ACE levels were significantly elevated, and cardiac ACE2 levels were significantly decreased. ACE inhibitor did not change serum FGF23 levels but significantly decreased cardiac FGF23 levels with improvements in LVH and RAAS-related factors, while FGFR4 inhibitor did not change the values.

Conclusions

Not serum FGF23 but cardiac FGF23 levels and RAAS parameters significantly changed in the early stage of LVH without chronic kidney disease. RAAS blockade might be more crucial than FGF23 blockade for preventing LVH progression in this condition.
Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review
Authors: Xie Xueqin , Wu Changchun , Hao Yuduo , Wang Tianyu , Yang Yuhe , Cai Peiling , Zhang Yang , Huang Jian , Deng Kejun , Yan Dan , Lin Hao
Published: December 2023

Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
Characterization of circulating extracellular traps and immune responses to citrullinated LL37 in psoriasis
Authors: Martín Monreal María Teresa , Kvist-Hansen Amanda , Massarenti Laura , Steffensen Rudi , Loft Nikolai , Hansen Peter Riis , Ødum Niels , Skov Lone , Nielsen Claus H.
Published: December 2023

Background

The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role in the pathogenesis of the disease. Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, can be implicated in the formation of NETs. We hypothesized that citrullination increases LL37 immunogenicity and that NETs are a source of LL37.

Objectives

We aimed to characterize cytokine responses of B cells and T cells to native and citrullinated LL37 (citLL37) and determine the prevalence and composition of circulating NETs in patients with psoriasis and healthy blood donors (HDs).

Methods

Mononuclear cells (MNCs) and serum were isolated from 20 HDs and 20 patients with psoriasis. The MNCs were stimulated with native LL37 and citLL37 and the proportion of cytokine-positive B cells and T cells was determined by flow cytometry. Circulating antibodies against native LL37 and citLL37 as well as circulating NETs were measured by ELISA, as was the content of LL37, citLL37, and IgG in the NETs.

Results

CitLL37, but not native LL37, induced IFN-γ-production by T cells and B cells from psoriasis patients, as well as IL-10-production by the patients’ CD4+ T cells. Serum from 40% of patients and 55% of HDs contained circulating NETs, of which 63% and 27%, respectively, contained LL37. Only two patients had NETs containing citLL37 and IgG antibodies were found in NETs from three patients and one HD. Post-hoc analysis of the cytokines produced by B cells and T cells after stimulation with citLL37 revealed two clusters of patients consisting of 10 high-responders and 9 low-responders. The high-responders were those that had circulating NETs in combination with an earlier age of onset of the disease.

Conclusion

Citrullinated but not native LL37 elicits IFN-γ-responses by T cells and B cells from psoriasis patients, particularly those with circulating NETs and early disease onset, suggesting a role of citLL37 as an autoantigen in this subgroup of patients.
Non-glycosylated G protein with CpG ODN provides robust protection against respiratory syncytial virus without inducing eosinophilia
Authors: Kawahara Eigo , Shibata Takehiko , Hirai Toshiro , Yoshioka Yasuo
Published: December 2023

Introduction

Respiratory syncytial virus (RSV) vaccines targeting the fusion glycoprotein (F protein) are highly effective clinically in preventing RSV challenges. The attachment glycoprotein (G protein) is a potentially effective vaccine antigen candidate, as it is important for cell adhesion during infection. However, vaccine-associated enhanced diseases in mice, such as eosinophilic lung inflammation following RSV challenge, are a concern with G protein vaccines. This study aimed to design an effective G protein vaccine with enhanced safety and efficacy by evaluating the efficacy and adverse reactions of vaccines composed of different recombinant G proteins and adjuvants in mice.

Methods

Mice were subcutaneously immunized with glycosylated G protein expressed in mammalian cells (mG), non-glycosylated G protein expressed in Escherichia coli (eG), or F protein with or without aluminum salts (alum), CpG oligodeoxynucleotide (CpG ODN), or AddaVax. After vaccination, the levels of G-specific antibody and T-cell responses were measured. The immunized mice were challenged with RSV and examined for the viral load in the lungs and nasal turbinates, lung-infiltrating cells, and lung pathology.

Results

mG with any adjuvant was ineffective at inducing G-specific antibodies and had difficulty achieving both protection against RSV challenge and eosinophilia suppression. In particular, mG+CpG ODN induced G-specific T helper 1 (Th1) cells but only a few G-specific antibodies and did not protect against RSV challenge. However, eG+CpG ODN induced high levels of G-specific antibodies and Th1 cells and protected against RSV challenge without inducing pulmonary inflammation. Moreover, the combination vaccine of eG+F+CpG ODN showed greater protection against upper respiratory tract RSV challenge than using each single antigen vaccine alone.

Discussion

These results indicate that the efficacy of recombinant G protein vaccines can be enhanced without inducing adverse reactions by using appropriate antigens and adjuvants, and their efficacy is further enhanced in the combination vaccine with F protein. These data provide valuable information for the clinical application of G protein vaccines.
Immunotherapy, targeted therapy, and their cross talks in hepatocellular carcinoma
Authors: Liu Jun , Park Kevin , Shen Ziyang , Lee Hannah , Geetha Purnima , Pakyari Mohammadreza , Chai Li
Published: December 2023

Hepatocellular carcinoma (HCC) is a challenging malignancy with limited treatment options beyond surgery and chemotherapy. Recent advancements in targeted therapies and immunotherapy, including PD-1 and PD-L1 monoclonal antibodies, have shown promise, but their efficacy has not met expectations. Biomarker testing and personalized medicine based on genetic mutations and other biomarkers represent the future direction for HCC treatment. To address these challenges and opportunities, this comprehensive review discusses the progress made in targeted therapies and immunotherapies for HCC, focusing on dissecting the rationales, opportunities, and challenges for combining these modalities. The liver’s unique physiology and the presence of fibrosis in many HCC patients pose additional challenges to drug delivery and efficacy. Ongoing efforts in biomarker development and combination therapy design, especially in the context of immunotherapies, hold promise for improving outcomes in advanced HCC. Through exploring the advancements in biomarkers and targeted therapies, this review provides insights into the challenges and opportunities in the field and proposes strategies for rational combination therapy design.
Machine learning to identify risk factors associated with the development of ventilated hospital-acquired pneumonia and mortality: implications for antibiotic therapy selection
Authors: Sophonsri Anthony , Lou Mimi , Ny Pamela , Minejima Emi , Nieberg Paul , Wong-Beringer Annie
Published: December 2023

Background

Among patients with nosocomial bacterial pneumonia, those who decompensated to requiring mechanical ventilation (vHABP) faced the highest mortality followed by ventilator-associated pneumonia (VABP) and non-ventilated hospital-acquired pneumonia (nvHABP). The objectives of this study were to identify risk factors associated with the development and mortality of vHABP and to evaluate antibiotic management.

Methods

A multicenter retrospective cohort study of adult inpatients with nosocomial pneumonia during 2014–2019 was performed. Groups were stratified by vHABP, nvHABP, and VABP and compared on demographics, clinical characteristics, treatment, and outcomes. Multivariable models were generated via machine learning to identify risk factors for progression to vHABP as well as pneumonia-associated mortality for each cohort.

Results

457 patients (32% nvHABP, 37% vHABP, and 31% VABP) were evaluated. The vHABP and nvHABP groups were similar in age (median age 66.4 years) with 77% having multiple comorbidities but more vHABP patients had liver disease (18.2% vs. 7.7% p = 0.005), alcohol use disorder (27% vs. 7.1%, p < 0.0001), and were hospitalized within the past 30  days (30.4% vs. 19.5%, p = 0.02). An immediate need for ventilatory support occurred in 70% of vHABP patients on the day of diagnosis. Mortality was the highest in vHABP followed by VABP and nvHABP groups (44.6% vs. 36% vs. 14.3%, p < 0.0001). Nearly all (96%) vHABP patients had positive cultures, with Gram-negative pathogens accounting for 58.8% whereby 33.0% were resistant to extended-spectrum β-lactams (ESBLs), ceftriaxone (17.5%), fluoroquinolones (20.6%), and carbapenems (12.4%). Up to half of the vHABP patients with ESBL-Enterobacterales or P. aeruginosa did not receive an effective empiric regimen; over 50% increase in mortality rate was observed among patients whom effective therapy was initiated past the day of pneumonia diagnosis. Risk factors associated with vHABP development were alcohol use disorder, APACHE II score, vasopressor therapy prior to infection, and culture positive for ESBL-Enterobacterales whereas history of hospitalization in the past 30  days, active malignancy, isolation of ceftriaxone-resistant pathogens or Pseudomonas aeruginosa, and vasopressor therapy were risk factors for vHABP-associated mortality.

Conclusion

Patients with vHABP experienced an acute and severe decompensation upon diagnosis. The risk factors identified in this study could provide actionable data for clinicians to identify those at risk for vHABP at the onset of pneumonia and to target antimicrobial stewardship efforts to improve treatment success.
Postbiotic production: harnessing the power of microbial metabolites for health applications
Authors: Prajapati Nidhi , Patel Jinil , Singh Sachidanand , Yadav Virendra Kumar , Joshi Chinmayi , Patani Anil , Prajapati Dharmendra , Sahoo Dipak Kumar , Patel Ashish
Published: December 2023

Postbiotics, which are bioactive substances derived from the metabolic processes of beneficial microbes, have received considerable attention in the field of microbiome science in recent years, presenting a promising path for exploration and innovation. This comprehensive analysis looks into the multidimensional terrain of postbiotic production, including an extensive examination of diverse postbiotic classes, revealing their sophisticated mechanisms of action and highlighting future applications that might significantly affect human health. The authors thoroughly investigate the various mechanisms that support postbiotic production, ranging from conventional fermentation procedures to cutting-edge enzyme conversion and synthetic biology approaches. The review, as an acknowledgment of the field’s developing nature, not only highlights current achievements but also navigates through the problems inherent in postbiotic production. In order to successfully include postbiotics in therapeutic interventions and the production of functional food ingredients, emphasis is given to critical elements, including improving yields, bolstering stability, and assuring safety. The knowledge presented herein sheds light on the expanding field of postbiotics and their potential to revolutionize the development of novel therapeutics and functional food ingredients.
Circular RNA and intervertebral disc degeneration: unravelling mechanisms and implications
Authors: Xie Guohao , Wu Tingrui , Ji Guangju , Wu Hang , Lai Yue , Wei Bo , Huang Wenhua
Published: December 2023

Low back pain (LBP) is a major public health problem worldwide and a significant health and economic burden. Intervertebral disc degeneration (IDD) is the reason for LBP. However, we have not identified effective therapeutic strategies to address this challenge. With accumulating knowledge on the role of circular RNAs in the pathogenesis of IDD, we realised that circular RNAs (circRNAs) may have tremendous therapeutic potential and clinical application prospects in this field. This review presents an overview of the current understanding of characteristics, classification, biogenesis, and function of circRNAs and summarises the protective and detrimental circRNAs involved in the intervertebral disc that have been studied thus far. This review is aimed to help researchers better understand the regulatory role of circRNAs in the progression of IDD, reveal their clinical therapeutic potential, and provide a theoretical basis for the prevention and targeted treatment of IDD.
Do neutrophil extracellular traps implicate in atheromatous plaques from carotid endarterectomy? Re-analyzes of cDNA microarray data by surgeons
Authors: Takahira Ryotaro , Ujifuku Kenta , Izumo Tsuyoshi , Xie Ang , Okamura Kazuaki , Morofuji Yoichi , Matsuo Takayuki
Published: December 2023

Background

Carotid artery stenosis is the cause of 15% of strokes. Neutrophil extracellular traps (NETs) and peptidyl arginine deiminase 4 (PAD4) are believed to be involved in thrombosis. This pilot study described the differential expression profile of NETs between atheromatous plaques and surrounding tissues.

Methods

Microarray datasets of carotid plaques were obtained from Gene Expression Omnibus. The normalized data were processed into comma-separated value matrix files using spreadsheet software. Analyzes of microarray data were conducted using integrated differential expression and pathway analysis.

Result

The clustering results illustrated that the classifications of plaque and control had reasonable biological validity. Pathway analysis revealed the relevance of immune response, cell signaling, and other pathways. Differentially expressed genes were detected between carotid plaques and control specimens. However, enrichment analyzes did not reveal a difference in PAD4 expression between the groups and that NET implication was only found in one cDNA microarray dataset.

Discussion

This pilot study does not necessarily dismiss the possibility of a relationship between NETs and atherothrombotic stroke. Gene expression could differ between endothelial cells and atheromas, and further studies are needed.
Pattern of neurological recovery in persons with an acute cervical spinal cord injury over the first 14 days post injury
Authors: Fallah Nader , Noonan Vanessa K. , Waheed Zeina , Charest-Morin Raphaele , Dandurand Charlotte , Cheng Christiana , Ailon Tamir , Dea Nicolas , Paquette Scott , Street John T. , Fisher Charles , Dvorak Marcel F. , Kwon Brian K.
Published: December 2023

Introduction

Following a traumatic spinal cord injury (SCI) it is critical to document the level and severity of injury. Neurological recovery occurs dynamically after injury and a baseline neurological exam offers a snapshot of the patient's impairment at that time. Understanding when this exam occurs in the recovery process is crucial for discussing prognosis and acute clinical trial enrollment. The objectives of this study were to: (1) describe the trajectory of motor recovery in persons with acute cervical SCI in the first 14 days post-injury; and (2) evaluate if the timing of the baseline neurological assessment in the first 14 days impacts the amount of motor recovery observed.

Methods

Data were obtained from the Rick Hansen Spinal Cord Injury Registry (RHSCIR) site in Vancouver and additional neurological data was extracted from medical charts. Participants with a cervical injury (C1–T1) who had a minimum of three exams (including a baseline and discharge exam) were included. Data on the upper-extremity motor score (UEMS), total motor score (TMS) and American Spinal Injury Association (ASIA) Impairment Scale (AIS) were included. A linear mixed-effect model with additional variables (AIS, level of injury, UEMS, time, time2, and TMS) was used to explore the pattern and amount of motor recovery over time.

Results

Trajectories of motor recovery in the first 14 days post-injury showed significant improvements in both TMS and UEMS for participants with AIS B, C, and D injuries, but was not different for high (C1–4) vs. low (C5–T1) cervical injuries or AIS A injuries. The timing of the baseline neurological examination significantly impacted the amount of motor recovery in participants with AIS B, C, and D injuries.

Discussion

Timing of baseline neurological exams was significantly associated with the amount of motor recovery in cervical AIS B, C, and D injuries. Studies examining changes in neurological recovery should consider stratifying by severity and timing of the baseline exam to reduce bias amongst study cohorts. Future studies should validate these estimates for cervical AIS B, C, and D injuries to see if they can serve as an “adjustment factor” to control for differences in the timing of the baseline neurological exam.
Luxembourg Parkinson’s study -comprehensive baseline analysis of Parkinson’s disease and atypical parkinsonism
Authors: Pavelka Lukas , Rawal Rajesh , Ghosh Soumyabrata , Pauly Claire , Pauly Laure , Hanff Anne-Marie , Kolber Pierre Luc , Jónsdóttir Sonja R. , Mcintyre Deborah , Azaiz Kheira , Thiry Elodie , Vilasboas Liliana , Soboleva Ekaterina , Giraitis Marijus , Tsurkalenko Olena , Sapienza Stefano , Diederich Nico , Klucken Jochen , Glaab Enrico , Aguayo Gloria A. , Jubal Eduardo Rosales , Perquin Magali , Vaillant Michel , May Patrick , Gantenbein Manon , Satagopam Venkata P. , Krüger Rejko ,   on behalf of the NCER-PD Consortium
Published: December 2023

Background

Deep phenotyping of Parkinson’s disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson’s study.

Objective

To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls.

Methods

Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders.

Results

The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003).

Conclusion

Luxembourg Parkinson’s study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.

Clinical trial registration: clinicaltrials.gov, NCT05266872.
The neural mechanisms underlying the processing of consonant, vowel and tone during Chinese typing: an fNIRS study
Authors: Yu Jianan , Zou Yun , Wu Yan
Published: December 2023

Many studies have explored the role of consonant, vowel, and tone in Chinese word identification or sentence comprehension. However, few studies have explored their roles and neural basis during Chinese word production, especially when involving neural basis. The present fNIRS study investigated the neural mechanisms of consonant, vowel, and tone processing during Chinese typing. Participants were asked to name the Chinese characters displayed on a computer screen by typing on a keyboard while hearing a simultaneously presented auditory stimulus. The auditory stimulus was either consistent with the characters’ pronunciation (consistent condition) or mismatched in the consonant, vowel, or tone of the character pronunciation. The fNIRS results showed that compared with the consistent condition (as baseline), the consonant mismatch condition evoked lower levels of oxygenated hemoglobin (HbO) activation in the left inferior frontal gyrus Broca’s triangle and left superior temporal gyrus. Vowel mismatch condition evoked a higher level of HbO activation in the top of the left inferior frontal gyrus and left middle frontal gyrus. The regions and patterns of brain activation evoked by tone mismatch were the same as those of vowel mismatch. The study indicated that consonant, vowel and tone all play a role in Chinese character production. The sensitive brain areas were all in the left hemisphere. However, the neural mechanism of consonant processing differed from vowel processing in both brain regions and patterns, while tone and vowel processing shared the same regions.
Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities
Authors: Vastrad Soujanya J. , Ritesh Giri , V Sowmya S. , Saraswathy Ganesan Rajalekshmi , Augustine Dominic , Alzahrani Khalid J. , Alzahrani Fuad M. , Halawani Ibrahim F. , Ashi Heba , Alshahrani Mohammed , Hassan Reem Nabil , Baeshen Hosam Ali , Saravanan Kamatchi Sundara , Satish Kshreeraja S. , Vutukuru Pravallika , Patil Shankargouda
Published: December 2023

The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell’s pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.
Case report: Parsonage-turner syndrome in a melanoma patient treated by BRAF/MEK inhibitors after immune checkpoint inhibitors
Authors: Bonnefin Charlotte , Duval Fanny , Rouanet Marie , Kostine Marie , Gerard Emilie
Published: December 2023

Introduction

Combination molecular BRAF/MEK inhibitors targeted therapy has been shown to improve overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events but neurological adverse events (nAEs) remain rare.

Case report

A 42-year-old woman diagnosed with metastatic melanoma presented with an intense pain in the left shoulder 7 days after the beginning of encorafenib/binimetinib after immune checkpoint inhibitors (ICI) combination. No other triggering factors were identified. Electromyogram performed one month after the pain onset revealed a left brachial plexopathy suggestive of a Parsonage-Turner syndrome. The weakness slowly improved with intensive rehabilitation and targeted therapies were continued.

Conclusion

We report the first case of Parsonage-Turner syndrome in a melanoma patient treated with encorafenib/binimetinib following checkpoint inhibitors combination.

We cannot rule out the implication of ICI in the development of this syndrome but the rapid onset of the symptoms after the beginning of targeted therapies makes their involvment more likely.

Given the increased use of BRAF/MEK inhibitors in managing of stage III and IV melanoma, as well as the development in stage II, clinicians should be aware of this potential side effect.
Advances in the role of microRNAs associated with the PI3K/AKT signaling pathway in lung cancer
Authors: Wang Yanting , Zhang Tao , He Xin
Published: December 2023

Cancer has long been a topic of great interest in society and a major factor affecting human health. Breast, prostate, lung, and colorectal cancers are the top four tumor types with the greatest incidence rates in 2020, according to the most recent data on global cancer incidence. Among these, lung cancer had the highest fatality rate. Extensive research has shown that microRNAs, through different signaling pathways, play crucial roles in cancer development. It is considered that the PI3K/AKT signaling pathway plays a significant role in the development of lung cancer. MicroRNAs can act as a tumor suppressor or an oncogene by altering the expression of important proteins in this pathway, such as PTEN and AKT. In order to improve the clinical translational benefit of microRNAs in lung cancer research, we have generalized and summarized the way of action of microRNAs linked with the PI3/AKT signaling pathway in this review through literature search and data analysis.
Oral FXIIa inhibitor KV998086 suppresses FXIIa and single chain FXII mediated kallikrein kinin system activation
Authors: Clermont Allen C. , Murugesan Nivetha , Edwards Hannah J. , Lee Daniel K. , Bayliss Natasha P. , Duckworth Edward J. , Pethen Stephen J. , Hampton Sally L. , Gailani David , Feener Edward P.
Published: December 2023

Background: The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic activities of FXIIa and single-chain Factor XII (FXII) zymogen contribute to KKS activation and thereby may play roles in both initiating and propagating HAE attacks. In this report, we investigated the effects of potent small molecule FXIIa inhibitors on FXIIa and single chain FXII enzymatic activities, KKS activation, and angioedema in mice.

Methods: We examined the effects of 29 structurally distinct FXIIa inhibitors on enzymatic activities of FXIIa and a mutant single chain FXII with R334A, R343A and R353A substitutions (rFXII-T), that does not undergo zymogen conversion to FXIIa, using kinetic fluorogenic substrate assays. We examined the effects of a representative FXIIa inhibitor, KV998086, on KKS activation and both carrageenan- and captopril-induced angioedema in mice.

Results: FXIIa inhibitors designed to target its catalytic domain also potently inhibited the enzymatic activity of rFXII-T and the pIC50s of these compounds linearly correlated for rFXIIa and rFXII-T (R2 = 0.93). KV998086, a potent oral FXIIa inhibitor (IC50 = 7.2 nM) inhibited dextran sulfate (DXS)-stimulated generation of plasma kallikrein and FXIIa, and the cleavage of high molecular weight kininogen (HK) in human plasma. KV998086 also inhibited rFXII-T mediated HK cleavage (p < 0.005) in plasma from FXII knockout mice supplemented with rFXII-T and stimulated with polyphosphate or DXS. Orally administered KV998086 protected mice from 1) captopril-induced Evans blue leakage in colon and laryngotracheal tissues and 2) blocked carrageenan-induced plasma HK consumption and paw edema.

Conclusion: These findings show that small molecule FXIIa inhibitors, designed to target its active site, also inhibit the enzymatic activity of FXII zymogen. Combined inhibition of FXII zymogen and FXIIa may thereby suppress both the initiation and amplification of KKS activation that contribute to hereditary angioedema attacks and other FXII-mediated diseases.
Translation of preclinical ethnomedicine data in LMICs: the example of rooibos
Authors: Pretorius Lesha , Smith Carine
Published: December 2023

All disease, but especially non-communicable diseases, are related to dysfunction of one or more regulatory systems. In developing countries, long-term management of patients with chronic diseases has many challenges and is generally not financially viable, but Africa in particular, which is rich in diverse ethnomedicines presents a more feasible long-term therapeutic approach in this niche. However, despite comprehensive preclinical investigations on numerous plant-derived candidate medicines, only a small portion of these reach the patient as recognised medicines. In this review, we use the example of rooibos (Aspalathus linearis (Burm.f.) R. Dahlgren)–which is globally consumed as aromatic, caffeine-free tea–to illustrate the hurdles that need to be overcome in the low-to middle-income countries, before progression of ethnomedicines to official treatment regimens can be achieved. In terms of methodology, regulatory system focused rooibos papers indexed on PubMed for the past three decades (n = 112) were accessed. Papers reporting duplication of previous results were excluded, as well as review papers. Topics covered includes the high standard of ethnomedicine drug discovery and efficacy testing research performed in Africa (and South Africa in particular in the case of rooibos), the potential bias in terms of preclinical research focus, ethnomedicine ownership and the requirement for independent clinical trial coordination and/or management.