bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of carglumic acid in the long-term management of propionic and methylmalonic acidurias
Authors: Yap Sufin , Gasperini Serena , Matsumoto Shirou , Feillet François
Published: December 2024

Propionic aciduria (PA) and methylmalonic aciduria (MMA) are rare inherited disorders caused by defects in the propionate metabolic pathway. PA due to propionyl coenzyme A carboxylase deficiency results in accumulation of propionic acid, while in MMA, deficiency in methylmalonyl coenzyme A mutase leads to accumulation of methylmalonic acid. Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle. Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA. CGA is well tolerated and its use in normalizing ammonia levels during acute hyperammonemic episodes in patients with PA and MMA is well established. This expert opinion analyzed clinical evidence for CGA and discussed its place, along with other management strategies, in the long-term management of PA or MMA. A literature search of PubMed was undertaken to identify publications related to the chronic use of CGA, transplantation, dietary management, ammonia scavengers, and gene therapy for treatment of patients with PA or MMA. The authors selected the most relevant studies for inclusion. Four clinical studies, one single center case series, and three case reports show that CGA is safe and effective in the chronic treatment of PA and MMA. In particular, the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone. Current treatment guidelines and recommendations include the use of CGA mainly in acute decompensation, however, lag in considering the benefits of long-term CGA treatment on clinical and biochemical outcomes in patients with PA or MMA. CGA is safe and effective in the chronic treatment of PA and MMA and may help to resolve some of the issues associated with other strategies used to treat these disorders. Thus, CGA appears to have potential for the chronic management of patients with PA and MMA and should be recommended for inclusion in the chronic treatment of these disorders.
Guanidinoacetic acid supplementation and stocking density effects on broiler performance: behavior, biochemistry, immunity, and small intestinal histomorphology
Authors: Alaa Mohammad , Abdel Razek Abeer Hamada , Tony Mohamed Ahmed , Yassin Aya Mohye , Warda Mohamad , Awad Mohamed Ahmed , Bawish Basma Mohamed
Published: December 2024

Background

Rearing poultry under stressful high stocking density (HSD) conditions is a common commercial practice to increase profitability, despite its negative effects on broiler physiology and welfare. Many feed additives are used to alleviate the negative impact of such practices. This study investigated the ameliorative effects of guanidinoacetic acid (GAA) on growth performance, ingestive behavior, immune response, antioxidant status, stress indicators, and intestinal histomorphometry of broilers subjected to HSD. A total of 364 male broilers were randomly allocated into four treatments with 7 replicates each in a 2 × 2 factorial arrangement: two stocking densities (SD) (10 and 16 birds/m2) and two GAA levels (0 and 0.6 g/kg feed).

Results

Body weight, weight gain, feed intake, feed conversion ratio, production efficiency factor, dressing yield, and ingestive behavior were negatively affected by HSD, whereas the mortality rate was unaffected (P > 0.05). GAA improved the overall growth performance and dressing percentage (P < 0.05). In the HSD group, the immune response decreased at d 21 (P < 0.05). Creatine kinase, glutathione peroxidase (GPX), superoxide dismutase, catalase, triglycerides, and villus length and width (ileum) were reduced, whereas corticosterone (CORT) was increased (P < 0.05). Moreover, GAA increased the hemagglutination-inhibition titer at 21 days and the levels of lactate dehydrogenase, GPX, and catalase and decreased the levels of creatinine, alanine aminotransferase, nitrite, triglycerides, and CORT (P < 0.05). SD and GAA did not affect malondialdehyde or other biochemical parameters (P > 0.05).

Conclusions

Dietary GAA supplementation can improve productivity and antioxidant status and reduce stress in broilers reared in a HSD environment.
Temporal trends and social inequities in adolescent and young adult mental health disorders in Catalonia, Spain: a 2008–2022 primary care cohort study
Authors: Lozano-Sánchez Ana , Aragonès Enric , López-Jiménez Tomàs , Bennett Matthew , Evangelidou Stella , Francisco Esther , García Myriam , Malgosa Estel , Codern-Bové Núria , Guzmán-Molina Claudia , Jacques-Aviñó Constanza
Published: December 2024

Background

The prevalence of mental health disorders in children, teens, and young adults is rising at an alarming rate. This study aims to explore time trends in the incidence of mental disorders among young people in Catalonia, Spain from 2008 to 2022, focusing on the effects of the COVID-19 pandemic and from the perspective of social inequities.

Methods

A cohort study using primary care records from the SIDIAP database was conducted. It included 2,088,641 individuals aged 10 to 24 years. We examined the incidence of depressive, anxiety, eating, and attention deficit/hyperactivity disorders, stratified by sex, age, deprivation, and nationality.

Results

All disorders reflected an increasing trend throughout the study period: depressive disorders (IRR: 2.44, 95% CI: 2.31–2.59), anxiety disorders (IRR: 2.33, 95% CI: 2.27–2.39), ADHD (IRR: 2.33, 95%CI: 2.17–2.50), and eating disorders (IRR: 3.29, 95% CI: 3.01–3.59). A significant increase in incidence was observed after the outbreak of the COVID-19 pandemic. In 2022, anxiety disorders were most frequent, with an incidence rate (IR) of 2,537 per 100,000 persons-year (95% CI: 2,503–2,571). Depressive disorders followed with an IR of 471 (95% CI: 458–486), ADHD with an IR of 306 (95% CI: 295–317) and eating disorders with an IR of 249 (95% CI: 239–259). Significant associations were reported with sex, age, deprivation, and nationality.

Conclusion

The incidence of all studied disorders has steadily increased, reaching unprecedented levels during the pandemic. Understanding these trends is essential for an appropriate healthcare response, while addressing the non-medical determinants, requires action across all sectors of society.
Navigating recovery in childhood OCD: a qualitative analysis of barriers and facilitators
Authors: Sravanti Lakshmi , Madegowda Rajendra Kiragasur , Velusamy Arul Jayendra Pradeep , Kommu John Vijay Sagar , Girimaji Satish Chandra , Seshadri Shekhar
Published: December 2024

Objective

The objective is to examine barriers and facilitators to recovery in children and adolescents with obsessive-compulsive disorder (OCD) using a qualitative approach.

Methods

Ten semi-structured interviews were conducted, audio-recorded, and analyzed using thematic analysis. Findings were validated through investigator triangulation, peer validation and member check.

Results

Barriers to recovery were internal—lack of awareness; poor motivation to seek treatment; and perceived stigma, or external—poor parental support; parental anxiety; inadequate awareness in schools; social misconceptions about illness; myths about medication; and frustrations in treatment processes. Facilitators were internal—will and determination; self-discipline; keeping calm; sense of purpose, and external—general awareness; parental support; peer support; and good therapeutic engagement.

Conclusions

To the best of our knowledge, this is the first study to explore barriers and facilitators to recovery in-depth in pediatric OCD. Findings underscore the importance of tailored interventions, robust support networks, and cultural sensitivity for successful recovery outcomes.
Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes
Authors: Stanaway Ian B. , Morrell Eric D. , Mabrey F. Linzee , Sathe Neha A. , Bailey Zoie , Speckmaier Sarah , Lo Jordan , Zelnick Leila R. , Himmelfarb Jonathan , Mikacenic Carmen , Evans Laura , Wurfel Mark M. , Bhatraju Pavan K.
Published: December 2024

Background

Patients with sepsis-induced AKI can be classified into two distinct sub-phenotypes (AKI-SP1, AKI-SP2) that differ in clinical outcomes and response to treatment. The biologic mechanisms underlying these sub-phenotypes remains unknown. Our objective was to understand the underlying biology that differentiates AKI sub-phenotypes and associations with kidney outcomes.

Methods

We prospectively enrolled 173 ICU patients with sepsis from a suspected respiratory infection (87 without AKI and 86 with AKI on enrollment). Among the AKI patients, 66 were classified as AKI-SP1 and 20 as AKI-SP2 using a three-plasma biomarker classifier. Aptamer-based proteomics assessed 5,212 proteins in urine collected on ICU admission. We compared urinary protein abundances between AKI sub-phenotypes, conducted pathway analyses, tested associations with risk of RRT and blood bacteremia, and predicted AKI-SP2 class membership using LASSO.

Measurement and main results

In total, 117 urine proteins were higher in AKI-SP2, 195 were higher in AKI-SP1 (FDR < 0.05). Urinary proteins involved in inflammation and chemoattractant of neutrophils and monocytes (CXCL1 and REG3A) and oxidative stress (SOD2) were abundant in AKI-SP2, while proteins involved in collagen deposition (GP6), podocyte derived (SPOCK2), proliferation of mesenchymal cells (IL11RA), anti-inflammatory (IL10RB and TREM2) were abundant in AKI-SP1. Pathways related to immune response, complement activation and chemokine signaling were upregulated in AKI-SP2 and pathways of cell adhesion were upregulated in AKI-SP1. Overlap was present between urinary proteins that differentiated AKI sub-phenotypes and proteins that differentiated risk of RRT during hospitalization. Variable correlation was found between top aptamers and ELISA based protein assays. A LASSO derived urinary proteomic model to classify AKI-SP2 had a mean AUC of 0.86 (95% CI: 0.69–0.99).

Conclusion

Our findings suggest AKI-SP1 is characterized by a reparative, regenerative phenotype and AKI-SP2 is characterized as an immune and inflammatory phenotype associated with blood bacteremia. We identified shared biology between AKI sub-phenotypes and eventual risk of RRT highlighting potential therapeutic targets. Urine proteomics may be used to non-invasively classify SP2 participants.
A hybrid epithelial-mesenchymal transition program enables basal epithelial cells to bypass stress-induced stasis and contributes to a metaplastic breast cancer progenitor state
Authors: Caruso Joseph A. , Chen-Tanyolac Chira , Tlsty Thea D.
Published: December 2024

Background

Human mammary epithelial cell (HMEC) cultures encounter a stress-associated barrier termed stasis, during which most cells adopt a senescence-like phenotype. From these cultures, rare variants emerge from the basal epithelial population, re-initiating growth. Variants exhibit pre-malignant properties, including an aberrant epigenetic program that enables continued proliferation and acquisition of genetic changes. Following oncogenic transformation, variants produce tumors that recapitulate the histopathological characteristics of metaplastic breast cancer (MBC), a rare and aggressive subtype marked by the differentiation of neoplastic epithelium into squamous and mesenchymal elements.

Methods

Using a serum-free HMEC culture system, we probed the capacity for phenotypic plasticity inherent to basal epithelial cell populations from human breast tissue as they navigated stasis and emerged as variant populations.

Results

We observed robust activation of a TGF-β-dependent epithelial-mesenchymal transition (EMT) program in basal epithelial cells during stasis, followed by subsequent attenuation of this program in emerging variants. Inhibition of the TGF-β pathway or depleting the EMT regulators Snail or Slug allowed basal epithelial cells to collectively bypass stasis, demonstrating that cellular dysfunction and arrest resulting from TGF-β and EMT activation are central to this in vitro barrier. The spontaneous emergence of variants from stasis cultures was associated with a restricted EMT trajectory, characterized by the stabilization of hybrid EMT states associated with greater proliferative capacity, rather than progressing to a complete mesenchymal state characterized by irreversible growth arrest. Epigenetic mechanisms, which contributed to the dysregulated growth control characteristic of the variant phenotype, also contributed to the stability of the hybrid EMT program in variants. By overcoming the cellular dysfunction and growth arrest resulting from TGF-β and complete EMT, variants exhibited a higher oncogenic transformation efficiency compared to pre-stasis basal epithelial cells. Inhibiting the TGF-β pathway prior to stasis significantly reduced EMT in the basal epithelial population, alleviated selective pressure driving variant emergence, and also enhanced oncogenic transformation efficiency, resulting in tumors with markedly diminished metaplastic differentiation.

Conclusions

This study reveals how an epigenetic program governs basal epithelial cell fate decisions and contributes to the development of MBC progenitors by restricting access to terminal mesenchymal states that induce growth arrest and, instead, favoring hybrid EMT states with enhanced tumorigenic potential.
Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: a single-center real-world study
Authors: Bae Soong June , Kim Jee Hung , Kim Min Ji , Kook Yoonwon , Baek Seung Ho , Kim Jung Hyun , Moon Sohyun , Lee Seung Eun , Jeong Joon , Cha Yoon Jin , Ahn Sung Gwe
Published: December 2024

Background

Immunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-world study in TNBC patients treated with neoadjuvant chemotherapy to compare pathologic complete response (pCR) rates relative to stromal tumor-infiltrating lymphocytes (sTIL) across different regimens: non-carboplatin, carboplatin-, and pembrolizumab-chemotherapy.

Patients and methods

We analyzed a cohort of 450 patients with TNBC who underwent surgery following neoadjuvant chemotherapy between March 2007 and February 2024. Treatment groups included 247 non-carboplatin, 120 carboplatin, and 83 pembrolizumab-chemotherapy recipients. sTIL was evaluated in biopsied samples. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with high sTIL (≥ 50%).

Results

The pCR rates were 32% in the non-carboplatin-, 57% in the carboplatin-, and 64% in the pembrolizumab-chemotherapy group. Ninety-two patients (20.4%) had LPBC. In LPBC, the pCR rates did not increase with the addition of carboplatin (50.0% in the non-carboplatin and 41.7% in carboplatin) but reached 83.3% with the addition of pembrolizumab and carboplatin. Among the non-LPBC, the pCR rate increased from 26.7 to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 61.2%, respectively).

Conclusions

In LPBC patients, the addition of carboplatin did not result in an elevated pCR rate; however, the addition of pembrolizumab tended to raise the pCR rate. In non-LPBC, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect.
Lay health coaching intervention for older adults with chronic diseases: study protocol for a pragmatic randomised controlled trial
Authors: Chung Edwin K. H. , Wong Eliza Lai-Yi , Leung Hera Hiu-Wah , Yeung Dannii Y. , Yeoh Eng-Kiong , Chen Frank Youhua
Published: December 2024

Background

A large proportion of older adults suffer from chronic diseases. Health coaching is a promising intervention that enhances individuals’ health knowledge and supports changes in health behaviours. Even though health professionals usually conduct health coaching interventions, lay health workers from different backgrounds account for a growing segment of health coaches over the years. The planned study’s main objective is to investigate whether health coaching by lay health workers is as effective as that by health professionals.

Methods

The effects of health coaching intervention by lay health workers will be examined in comparison with that by health professionals within a single-blind, multi-centre, randomised controlled trial with a follow-up assessment after 3 months. A total of 380 community-dwelling older adults with chronic diseases will be recruited and randomly assigned using a 1:1 ratio into the intervention and control groups. The intervention group will receive a 3-month health coaching intervention delivered by lay health workers, whereas the control group will receive the intervention delivered by health professionals. Primary outcomes include patient activation, physical activity and nutrition behaviours.

Discussion

The expected findings of this study will advance the health coaching literature, research and practice by determining whether health coaching by lay health workers is as effective as that by health professionals in enhancing older adults’ knowledge, skills and confidence in chronic disease self-management and promoting changes in health behaviours. If proven effective, the inclusion of lay health workers in delivering effective self-management interventions should be advocated to reduce the over-reliance on health professionals in the primary healthcare system.

Trial registration

ISRCTN, ISRCTN73836238. Registered 8 November 2023.
Chitosan/platinum nanocubes/Mn(TPDCA)2-modified glassy carbon electrodes for the electrochemical quantification of amlodipine in unprocessed plasma samples
Authors: Khadivi-Derakhshan Saeedeh , Abbasi Mohammad , Akbarzadeh Amirhossein , Pirouzmand Mahtab , Soleymani Jafar
Published: December 2024

A novel electrochemical probe is developed to detect amlodipine (AMD) in unprocessed plasma samples. The fabrication process involves the synthesis of platinum nanocubes (Pt NCs) and Mn(TPDCA)2 complexes, which are then immobilized them onto the glassy carbon electrode (GCE) surface. The developed electrochemical probe demonstrates exceptional detection performance, with a wide dynamic range, outstanding selectivity, and commendable reproducibility. The linear range and lower limit of detection of the developed method are 53 nM-3.5 µM and 53 nM, respectively. Electrochemical experiments have been conducted to study the kinetics of electrooxidation on the modified electrode, revealing that the process is diffusion-controlled. Furthermore, method validation studies are performed to assess the accuracy, precision, and selectivity of the sensor, demonstrating excellent performance in all these aspects. Consequently, it can be concluded that the sensor is highly suitable for practical applications in drug analysis.
Antimicrobial peptide production with Corynebacterium glutamicum on lignocellulosic side streams
Authors: Waldschitz Daniel , Neudert Mark-Richard , Kitzmüller Jakob , Bong Jae Hwi , Bus Yannick , Karner Eva Maria , Sinner Peter , Spadiut Oliver
Published: December 2024

Background

Biorefineries usually focus on the production of low-value commodities, such as bioethanol, platform chemicals or single cell protein. Shifting production to bioactive compounds, such as antimicrobial peptides, could provide an opportunity to increase the economic viability of biorefineries.

Results

Recombinant production of the antimicrobial peptide pediocin PA-1 in Corynebacterium glutamicum was transferred from yeast extract-based media to minimal media based on lignocellulosic spent sulfite liquor. Induced batch, fed batch, and extended batch process modes were compared for highest pediocin PA-1 production.

Conclusion

For pediocin PA-1 production on lignocellulosic residues, extended batch cultivation was identified as the optimal process mode, producing up to $$\simeq$$
≃
 104 mg/L active pediocin PA-1. Moreover, the production of pediocin PA-1 on this sustainable second generation resource exceeded its state-of-the-art production on yeast extract-based media $$\simeq$$
≃
 1.5-fold.
Right ventricular outflow tract doppler flow abnormalities suggestive of pulmonary embolism – case series and review
Authors: Ivičić Toni , Hamzić Jasmin , Radulović Bojana , Gornik Ivan
Published: December 2024

Background

Pulmonary embolism (PE) is one of the most challenging diagnoses in emergency medicine, mainly because symptoms range from asymptomatic disease to sudden death. The role of echocardiography in the workup of suspected PE has been supportive and used primarily to assess the right ventricular (RV) size and function, which is important for risk stratification. Several echocardiographic parameters described in the literature lack the desired accuracy. Recently, a potential value of less well-recognized RV outflow tract (RVOT) Doppler variables has been reported. The early systolic notching (ESN) pattern was observed in 92% of patients with high and intermediate risk PE, making it a promising sign in selected PE patients.

Case presentation

In this case series, we demonstrate a typical ESN pattern on RVOT Doppler evaluation in three patients with intermediate-risk PE presenting to our emergency department (ED). None of the patients had been previously diagnosed with pulmonary hypertension or other chronic pulmonary and cardiac disease. The pre-test probability was low. Massive proximal emboli were found on CT angiograms, involving pulmonary truncus or main pulmonary arteries. Previously, the ESN pattern was identified on a focused echocardiogram, which was the only echocardiographic indicator of increased pulmonary vascular resistance.

Conclusions

RVOT Doppler flow pattern of ESN has potential clinical utility for the detection of PE in ED patients. ESN could identify patients at higher risk, which are otherwise stratified as low risk according to the latest guidelines. Moreover, this case series illustrates that even in the absence of other echocardiographic findings of RV strain, the presence of ESN should alert to the possibility of acute PE. Further prospective studies are needed to assess its diagnostic value in a selected subgroup of patients, similar to the cases presented, that would have no other obvious reason for the altered RVOT Doppler curve.
Heat shock protein 70 enhances viral replication by stabilizing Senecavirus A nonstructural proteins L and 3D
Authors: Hou Lei , Zeng Penghui , Wu Zhi , Yang Xiaoyu , Guo Jinshuo , Shi Yongyan , Song Jiangwei , Zhou Jianwei , Liu Jue
Published: December 2024

Senecavirus A (SVA) is an emerging pathogen that causes idiopathic vesicular infections in pig herds, posing a potential threat to their production performance. Heat shock protein 70 (Hsp70) is a molecular chaperone that plays an important role in host homeostasis under both physiological and stress conditions. However, the effects of Hsp70 on SVA infection and its underlying regulatory mechanisms remain unclear. Here, we confirmed that Hsp70 expression promotes SVA infection, as evidenced by the expression of viral proteins, viral titers, and the number of rSVA-eGFP-infected cells. This positive regulatory role of Hsp70 is mainly involved in post-entry stages of SVA. Viral proteins that interacted with Hsp70 were screened, and co-immunoprecipitation (co-IP) shows an interaction between Hsp70 and SVA L and 3D proteins. Subsequently, we determined that the expression of Hsp70 is beneficial for the stability of the SVA L and 3D proteins. Additionally, the substrate-binding domain (SBD) of Hsp70 plays an important role in the interaction between Hsp70 and SVA L or 3D proteins; and the deletion of this domain results in the loss of the stabilizing effect of Hsp70 on SVA L and 3D proteins and the positive regulatory effect of Hsp70 on SVA replication. These results reveal that Hsp70 promotes SVA infection by stabilizing viral L and 3D proteins and provides a strategy for preventing and controlling SVA infection.
Revealing novel CD8+ T-cell epitopes from the H5N1 avian influenza virus in HBW/B1 haplotype ducks
Authors: Jiao Wanlin , Chen Yingyi , Xie Zimin , Zhao Li , Du Shanyao , Ma Mulin , Liao Ming , Dai Manman
Published: December 2024

The duck CD8+ T-cell response effectively defends against H5N1 highly pathogenic avian influenza virus (HPAIV) infection, but the recognized peptide is rarely identified. Here, we found that the ratio of CD8+ T cells and the expression of IFN-γ and cytotoxicity-associated genes, including granzyme A/K, perforin and IL2, at 7 days post-infection in peripheral blood mononuclear cells (PBMCs) from B1 haplotype ducks significantly increased in the context of defending against H5N1 AIV infection in vivo. Moreover, similar results were observed in cultured and sorted H5N1 AIV-stimulated duck CD8+ T cells in vitro. Next, we selected 109 epitopes as candidate epitopes on the basis of the MHC-I restriction binding peptide prediction website database and further identified twelve CD8+ T-cell epitopes that significantly increased IFN-γ gene expression after stimulating B1 haplotype duck memory PBMCs. In particular, NP338−346, NP473−481, M2−10, PB1540−548 and PA80−88 were highly conserved in H5N1, H5N6, H5N8, H7N9, and H9N2 AIVs. These findings provide directions for the development of universal T-cell epitope vaccines for AIV in ducks.
A spatially-heterogeneous impact of fencing on the African swine fever wavefront in the Korean wild boar population
Authors: Lim Jun-Sik , Vergne Timothée , Kim Eutteum , Guinat Claire , Dellicour Simon , Andraud Mathieu
Published: December 2024

In October 2019, South Korea’s first case of African swine fever (ASF) was reported in wild boar in the north of the country. Despite the implementation of a 2300 km-long fencing strategy, the ASF wavefront continued to invade southward. Our study aimed to investigate the ASF wavefront dynamics in different regions of South Korea, as well as to assess the effectiveness of the fencing measures on ASF dispersal and wavefront velocity. From the nationwide wild boar surveillance system, we extracted 2661 cases, starting from 2 October 2019 (first detection) to 15 September 2022. The cases were categorised into four main spatiotemporal clusters. The average wavefront velocity over the four clusters was estimated at 0.52 km/week, with the cluster in the eastern part of the Korean peninsula exhibiting the fastest velocity (0.99 km/week) compared to the other clusters (0.44, 0.31, and 0.15 km/week). We hypothesise that these differences are related to different wild boar densities due to heterogeneous habitat suitability. We also found that fencing significantly impacted ASF dispersal in only two of the four main clusters, with no evidence that fencing slowed down the spread of the wavefront in any of the clusters. We argue that this heterogeneity might result from fencing locations being misaligned with the true (and unobserved) wavefront.
Establishment of minigenomes for infectious bursal disease virus
Authors: Yang Hui , Zhang Mingrui , Wang Sanying , Peng Daxin , Martinez-Sobrido Luis , Ye Chengjin
Published: December 2024

Minigenomes (MGs) have greatly advanced research on the viral life cycle, including viral replication and transcription, virus‒host interactions, and the discovery of antivirals against RNA viruses. However, an MG for infectious bursal disease virus (IBDV) has not been well established. Here, we describe the development of IBDV MG, in which the entire coding sequences of viral genomic segments A and B are replaced with Renilla luciferase (Rluc) or enhanced green fluorescent protein (EGFP) reporter genes. Under the control of the RNA polymerase I promoter, the translation of IBDV MG is controlled by the viral proteins VP1 and VP3. Interestingly, IBDV B MG shows greater activity than does IBDV A MG. Moreover, the sense IBDV B MG was expressed at a higher level than the antisense IBDV B MG. In agreement with our previous findings, the translation of IBDV B MG controlled by VP1 and VP3 is independent of the cellular translation machinery components eukaryotic initiation factor (eIF)4E and eIF4G, but intact VP1 polymerase activity, VP3 dsRNA-binding activity, and the interaction between VP1 and VP3 are indispensable for both sense and antisense IBDV B MG activity. In addition, ribavirin, which inhibits IBDV replication, inhibits IBDV B MG activity in a dose-dependent manner. Collectively, the IBDV MG established in this study provides a powerful tool to investigate IBDV intracellular replication and transcription and virus‒host interactions and facilitates high-throughput screening for the identification of IBDV antivirals.
When animal viruses meet N6-methyladenosine (m6A) modifications: for better or worse?
Authors: Wang Wenjing , Jin Yufei , Xie Ziyun , He Mei , Li Jing , Wang Zihan , Ma Saiya , Zhang Wuchao , Tong Jie
Published: December 2024

N6-methyladenosine (m6A) is a prevalent and dynamic RNA modification, critical in regulating gene expression. Recent research has shed light on its significance in the life cycle of viruses, especially animal viruses. Depending on the context, these modifications can either enhance or inhibit the replication of viruses. However, research on m6A modifications in animal virus genomes and the impact of viral infection on the host cell m6A landscape has been hindered due to the difficulty of detecting m6A sites at a single-nucleotide level. This article summarises the methods for detecting m6A in RNA. It then discusses the progress of research into m6A modification within animal viruses’ infections, such as influenza A virus, porcine epidemic diarrhoea virus, porcine reproductive, and respiratory syndrome virus. Finally, the review explores how m6A modification affects the following three aspects of the replication of animal RNA viruses: the regulation of viral genomic RNA function, the alteration of the m6A landscape in cells after viral infection, and the modulation of antiviral immunity through m6A modification. Research on m6A modifications in viral RNA sheds light on virus-host interactions at a molecular level. Understanding the impact of m6A on viral replication can help identify new targets for antiviral drug development and may uncover novel regulatory pathways that could potentially enhance antiviral immune responses.
Development of a reporter feline herpesvirus-1 for antiviral screening assays
Authors: Yang Jia , Li Li , Xu Fuqiang , Jia Fan
Published: December 2024

Feline herpesvirus type 1 (FHV-1), a member of the Herpesviridae family, is one of the most important pathogens that causes upper respiratory tract disease in felines. Following infection, FHV-1 can spread retrogradely to the trigeminal ganglia, establishing a life-long latency. Although vaccines are available for routine feline vaccination, FHV-1 is still an agent that poses a serious threat to feline health. There are currently no specific drugs for the treatment of FHV-1. To facilitate the screening of antiviral drugs, we constructed a reporter FHV-1 virus, which expresses a secreted Gaussia luciferase (GLuc) and a bright green fluorescent protein, mNeonGreen. The reporter virus shows slower growth than does the wild-type FHV-1. The expression of the two reporter genes, Gluc and mNeonGreen, was consistent with viral propagation and remained stable during continuous passage in CRFK cells, even after twenty rounds. In addition, the known inhibitor ganciclovir was used to confirm the characteristics of the reporter virus for drug screening. We found that the reporter FHV-1 is suitable for antiviral screening assays. Overall, our work provides a useful tool for screening drugs to combat FHV-1.
The F204S mutation in adrenodoxin oxidoreductase drives salinomycin resistance in Eimeria tenella
Authors: Sun Pei , Wang Chaoyue , Xie Fujie , Chen Linlin , Zhang Yuanyuan , Tang Xinming , Hu Dandan , Gao Yang , Zhang Ning , Hao Zhenkai , Yu Yonglan , Suo Jingxia , Suo Xun , Liu Xianyong
Published: December 2024

Salinomycin is a polyether ionophore widely used for the treatment of coccidiosis in poultry. However, the emergence of coccidia strains resistant to salinomycin presents challenges for control efforts, and the mechanisms underlying this resistance in Eimeria remain inadequately understood. In this study, 78 stable salinomycin-resistant strains were generated through experimental evolution approaches. Whole-genome sequencing of salinomycin-resistant Eimeria tenella isolates revealed single nucleotide polymorphisms (SNPs), with 12 candidate genes harboring nonsynonymous mutations identified. To confirm the candidate gene responsible for conferring salinomycin resistance, we leveraged reverse genetic strategies and identified a key amino acid substitution (F204S) in adrenodoxin oxidoreductase (EtADR), which markedly reduced susceptibility to salinomycin. Our results elucidate the complex interactions among salinomycin resistance, parasite fitness, point mutations, and the structure of EtADR, laying the foundation for future studies on drug resistance in Eimeria and contributing to the development of targeted control strategies.
Expanding foresight methodology to better understand the unknown future and identify hard-to-predict events
Authors: Sytnik Veronica M. , Proskuryakova Liliana N.
Published: December 2024

This study focuses on the integration of methods from different theories and research concepts into futures studies in order to better understand the obscure future through the identification of unpredictable and hard-to-predict rare events and factors. Particular emphasis in this study is placed on systems theory, cybernetics, synergetics, theory of chaos, bifurcation theory, catastrophe theory, thermodynamics, and the theory of self-organized criticality that could elucidate the unknown and offer new insights to futures studies. White, black and grey swans, dragon kings, wild cards, and weak signals are rare and high-impact events commonly referred to in the risk management literature, synergetics, and futures studies. The academic literature does not always accurately identify commonalities and differences between them, as well as relevant research tools. This study clarifies the categories of unknown and types of uncertainty associated with these events, their characteristics, and the related existing foresight methods. It is also suggested to enrich foresight methodology by adding instruments from other disciplines.
Relationship between client laughter and session outcomes in metaverse counseling
Authors: Kang Jieun , Baek Woo Hyun , Jeong Yeon Bin , Yang Hyerin , Lee Seongchan , Lee Sang Min
Published: December 2024

Considering the growing interest in VR psychotherapy, this study investigated the relationship between client laughter and session outcomes in metaverse counseling. To investigate the relationships between types of client laughter and session outcomes in metaverse counseling, we employed a multilevel analysis by separating the variables into two levels: session-level (between-sessions) and client-level (between-clients). The dataset included 159 sessions nested among 26 clients. This study found that clients’ cheerful and nervous laughter positively impacted session outcomes at the session level (within individual clients). However, when considering client-level laughter events (between-client), nervous laughter at the session level was not significantly related to session outcomes. Polite, reflective, and contemptuous laughter showed no significant relationship with the session outcomes. None of the laughter events were related to session outcomes at the client level (between clients). However, there was a significant within-level interaction effect between session and cheerful laughter on session outcomes. The implications of the effects of client laughter are discussed in metaverse counseling by comparing them with those of in-person counseling.
BDNF augmentation reverses cranial radiation therapy-induced cognitive decline and neurodegenerative consequences
Authors: El-Khatib Sanad M. , Vagadia Arya R. , Le Anh C. D. , Baulch Janet E. , Ng Ding Quan , Du Mingyu , Johnston Kevin G. , Tan Zhiqun , Xu Xiangmin , Chan Alexandre , Acharya Munjal M.
Published: December 2024

Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6–7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.
Antioxidant, anti-acetylcholinesterase, and anti-amyloid-β peptide aggregations of hispolon and its analogs in vitro and improved learning and memory functions in scopolamine-induced ICR mice
Authors: Yang Chang-Hang , Li Cai-Wei , Sie Yi-Yan , Chen Liang-Chieh , Yuan Yu-Hsiang , Hou Wen-Chi
Published: December 2024

Background

Hispolon, one of bioactive phenolic compounds from a medicinal mushroom of sang-huang (Phellinus linteus) has been reported to exhibit anticancer and anti-inflammatory activities. The Alzheimer’s disease (AD) is ranked one of the top ten leading causes of death worldwide. Little is known about the effects of hispolon on delaying AD progression.

Results

The hispolon (No.1) and its six structural analogs (No.2 to No.7) were assayed by antioxidant, anti-acetylcholinesterase activities and anti-amyloid-β1-42-peptide aggregations. The No.1, No.6, and No.7 were selected for further molecular docking with acetylcholinesterase and core fragments of amyloid-β-peptide, and also showed capacities to recover cell viabilities in methylglyoxal-treated SH-SY5Y cells and also to enhance neurite outgrowths in PC12 cells. The daily pre-treatments of No.1, No.6, and No.7 for 10-days (40 mg/kg/day) showed to improve learning dysfunctions in scopolamine-induced ICR mice by passive avoidance tests.

Conclusion

The hispolon in the fungus sang-huang might be beneficial to develop functional foods or as lead compounds for treating degenerative disorders.
Long-term prevalence of PTSD symptom in family members of severe COVID-19 patients: a serial follow-up study extending to 18 months after ICU discharge
Authors: Nosaka Nobuyuki , Noguchi Ayako , Takeuchi Takashi , Wakabayashi Kenji
Published: December 2024

Background

Experiencing a loved one's stay in the intensive care unit (ICU) can profoundly affect families, often leading to post-intensive care syndrome-family (PICS-F), a condition particularly exacerbated during the COVID-19 pandemic. While PICS-F significantly impacts the mental health of families of ICU patients, especially in the context of COVID-19, the long-term effects beyond 12 months remain understudied. This study aims to explore the prevalence of PTSD-related symptoms and health-related quality of life (HRQOL) in family members up to 18 months after ICU discharge.

Methods

This prospective study, conducted in a tertiary university hospital in Tokyo, enrolled family members of severe COVID-19 ICU patients (July 2020 to June 2022 with final follow-up ending in December 2023). The primary outcome was family member symptoms of PTSD at 6, 12 and 18 months after ICU discharge, measured by the Impact of Events Scale-Revised (presence of PTSD symptoms defined by score > 24). Secondary outcomes were family member symptoms of anxiety and depression, sleep disorders, and health-related quality of life (HRQOL) at the same timepoint.

Results

Among 97 enrolled family members, 68 participated. At least one PTSD-related symptom was reported by 26% of family members, persisting over 18 months post-discharge (16% at 6 months, 23% at 12 months, and 25% at 18 months). A subgroup (15%) exhibited delayed-onset PTSD symptoms. Family members with PTSD-related symptoms reported lower HRQOL, especially in mental and social components.

Conclusions

The study underscores the importance of long-term support for family members post-ICU discharge, given the sustained prevalence of PTSD-related symptoms among family members of severe COVID-19 patients.
Evolution of the risk of death and hospitalisation in drivers involved in road crashes in spain, 1993–2020: an age-period-cohort analysis
Authors: Martín-delosReyes Luis Miguel , Martínez-Ruiz Virginia , Rivera-Izquierdo Mario , Jiménez-Mejías Eladio , Fernández Martínez Nicolás Francisco , Lardelli-Claret Pablo
Published: December 2024

Background

A prerequisite for understanding temporal changes in road crash severity is an unbiased description of this phenomenon. The aim of this study was to estimate the independent association trends of age, period and cohort with severity, encompassing the risk of death (RD) and the risk of death or hospitalisation (RDH) within 24 h, for drivers of passenger cars involved in road crashes with casualties in Spain from 1993 to 2020.

Methods

The study population comprised 2,453,911 drivers of passenger cars aged 18 to 98 years involved in road crashes included in the registers of the General Directorate of Traffic. Crash- and driver-related variables with sufficient continuity over time were included, establishing RD and RDH as study outcomes. Temporal trends of both outcomes were analysed using multivariable Poisson regression and multivariable age-period-cohort intrinsic estimator models. An additional sensitivity analysis was performed for the subset of single crashes.

Results

Severity estimates showed some variation across strategies. The APC model identified: (1) a J-shaped pattern for the effect of age on severity, (2) a decline in severity between 2001 and 2004 and 2013–2016, and (3) a birth cohort effect for both RD and RDH. In particular, the 1952–1958 cohort had the highest risk (RD = 1.17; 95%CI = 1.11–1.24 and RDH = 1.16; 95%CI = 1.13–1.19), followed by a decreasing trend in subsequent cohorts. Restricting the analysis to single crashes yielded similar results, with the exception of the age effect (severity increased with age). Furthermore, sex differences were observed–female sex was inversely associated with severity, especially for RD.

Conclusions

RD and RDH decreased during the first decade of the 21st century, but seemed to stabilise from 2013 onwards. Evidence from this study support that birth cohort is associated with road crash severity, independent of age and period. This cohort effect might be due, at least partially, to improvements in general and road safety education. Further studies are needed to elucidate the causes of our findings and to identify factors accounting for sex differences.
β3-Adrenergic receptor antagonism improves cardiac and vascular functions but did not modulate survival in a murine resuscitated septic shock model
Authors: Hagimont Eugénie , Lourenco-Rodrigues Marc-Damien , Chousterman Benjamin-Glenn , Yen-Potin Frances , Durand Manon , Kimmoun Antoine
Published: December 2024

Background

Recent findings suggest that β3-adrenergic receptors (β3-AR) could play a role in the hemodynamic regulation, but their function in septic shock remains unclear. This study investigates the modulation of β3-AR in an experimental murine model of resuscitated septic shock on in vivo hemodynamic, ex vivo vasoreactivity, inflammation and survival.

Method

Wild-type mice were used, undergoing cecal ligation and puncture (CLP) to induce septic shock, with SHAM as controls. Mice were treated with β3-AR agonist or antagonist three hours post-CLP, followed by resuscitation with fluids and antibiotics. Hemodynamic parameters were measured at 18 h following the surgery, and the expression of β-ARs in heart and aorta was assessed via immunostaining and western blot. Vascular reactivity was studied using myography, and inflammatory markers were analyzed through PCR and western blots. A 5-day survival study was conducted, documenting clinical severity scores and survival rates.

Results

β3-AR was expressed in both endothelial and myocardial cells in healthy and septic mice. During septic shock model, β3-AR density on endothelial cells increased post-CLP, while β1- and β2-AR decreased or remained constant. β3-AR antagonist treatment improved hemodynamic parameters, increasing mean arterial pressure and cardiac index, unlike the agonist. Vascular reactivity to phenylephrine was enhanced in aortic rings from both β3-AR agonist and antagonist-treated mice. However, no significant differences in inducible NO synthase expression were observed among treated groups. Despite improved hemodynamic parameters with β3-AR antagonist treatment, survival rates in treated groups remained similar to CLP group.

Conclusions

In an experimental murine model of resuscitated septic shock, β3-AR is resistant to desensitization and its inhibition improves cardiac and vascular function without affecting the short-term survival.
Clinical scoring systems, molecular subtypes and baseline [18F]FDG PET/CT image analysis for prognosis of diffuse large B-cell lymphoma
Authors: Sun Zhuxu , Yang Tianshuo , Ding Chongyang , Shi Yuye , Cheng Luyi , Jia Qingshen , Tao Weijing
Published: December 2024

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous hematological malignancy resulting in a range of outcomes, and the early prediction of these outcomes has important implications for patient management. Clinical scoring systems provide the most commonly used prognostic evaluation criteria, and the value of genetic testing has also been confirmed by in-depth research on molecular typing. [18F]-fluorodeoxyglucose positron emission tomography / computed tomography ([18F]FDG PET/CT) is an invaluable tool for predicting DLBCL progression. Conventional baseline image-based parameters and machine learning models have been used in prognostic FDG PET/CT studies of DLBCL; however, numerous studies have shown that combinations of baseline clinical scoring systems, molecular subtypes, and parameters and models based on baseline FDG PET/CT image may provide better predictions of patient outcomes and aid clinical decision-making in patients with DLBCL.