bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenges for unaccompanied asylum-seeking minors in Swedish compulsory institutional care
Authors: Stjerna Doohan Isabelle , Ghazinour Mehdi , Eriksson Malin , Padyab Mojgan , Sundqvist Johanna
Published: July 2024

This qualitative thematic study aimed to examine the placement of unaccompanied asylum-seeking minors in compulsory institutional care in Sweden, to expand knowledge regarding their care and treatment. The dataset comprised official documents and anonymized journal documents from personnel detailing the experiences of twenty-five unaccompanied asylum-seeking minors in compulsory institutional care organized by the Swedish National Board of Institutional Care in 2015. The study identified three main themes: traumatic life events and mental health, alignment between needs, goals, and treatment, and language difficulties. The findings revealed a high prevalence of severe traumatic experiences among the asylum-seeking minors, with half having endured significant psychological and physical trauma. Mental health issues were inconsistently addressed, and prior traumas were often overlooked in care planning. The majority exhibited various mental health problems, underscoring the need for tailored interventions. The study highlights challenges in aligning unaccompanied asylum-seeking minors' individual needs, treatment goals, and provided care. Language barriers emerged as a critical concern, impeding effective communication and treatment. Approximately 80% of the asylum-seeking minors experienced difficulties in understanding and expressing themselves in Swedish. The limited use of professional interpreters further exacerbated this issue. The study underscores the need for targeted interventions to better support unaccompanied asylum-seeking minors within compulsory institutional settings.
Advances in cellular and molecular pathways of salivary gland damage in Sjögren’s syndrome
Authors: Qi Wenxia , Tian Jiexiang , Wang Gang , Yan Yanfeng , Wang Tao , Wei Yong , Wang Zhandong , Zhang Guohua , Zhang Yuanyuan , Wang Jia
Published: July 2024

Sjögren’s Syndrome (SS) is an autoimmune disorder characterized by dysfunction of exocrine glands. Primarily affected are the salivary glands, which exhibit the most frequent pathological changes. The pathogenesis involves susceptibility genes, non-genetic factors such as infections, immune cells-including T and B cells, macrophage, dendritic cells, and salivary gland epithelial cells. Inflammatory mediators such as autoantibodies, cytokines, and chemokines also play a critical role. Key signaling pathways activated include IFN, TLR, BAFF/BAFF-R, PI3K/Akt/mTOR, among others. Comprehensive understanding of these mechanisms is crucial for developing targeted therapeutic interventions. Thus, this study explores the cellular and molecular mechanisms underlying SS-related salivary gland damage, aiming to propose novel targeted therapeutic approaches.
Differential response of IgM and IgG memory B cell populations to CD40L: insights of T cell – memory B cell interactions
Authors: Rincon-Arevalo Hector , Stefanski Ana-Luisa , Le Tuan Anh , Cases Marcos , Wiedemann Annika , Szelinski Franziska , Ritter Jacob , Dang Van Duc , Lino Andreia C. , Dörner Thomas , Schrezenmeier Eva
Published: July 2024

Memory B cells (mBCs) are characterized by their long-term stability, fast reactivation, and capability to rapidly differentiate into antibody-secreting cells (ASCs). However, the role of T cells in the differentiation of mBCs, in contrast to naive B cells, remains to be delineated. We study the role of T cells in mBC responses, using CD40L stimulation and autologous T-B co-cultures. Our results showed that increased CD40L levels led to a selective increased proliferation of IgM+ mBC, which did not class-switched, resulting in higher frequencies of IgM+ ASCs and a lower frequency of IgG+ ASCs. The IgG+/IgA+ mBCs were unaffected. We further compared the transcription of immune-related genes in IgM+ and IgG+ pre-plasmablasts cultured at high (500 ng/mL) and low (50 ng/mL) CD40L levels. In response to increased CD40L levels, both populations exhibited a core response to genes related to activation (TRAF1, AKT3, CD69, and CD80). However, they differed in genes related to cytokine/chemokine/homing interactions (CCL3/4/17, LTA, NKX2-3, BCL2 and IL21R) and cell-cell interactions (HLADR, CD40, and ICOSL), which were largely confined to IgG+ cells. Our findings revealed that in co-cultures with a high T-ratio, the response was similar to that found in cultures with high CD40L levels. These results suggest that IgG+ mBCs have a greater capacity for proliferation and T cell interaction, and weaker migration capabilities, leading to a preference for an IgG response over IgM in the short term. This adaptable response could fine-tune the memory repertoire with different functions of IgG versus IgM mBCs.
Exploring the pathogenesis of pulmonary vascular disease
Authors: Ejikeme Chidinma , Safdar Zeenat
Published: July 2024

Pulmonary hypertension (PH) is a complex cardiopulmonary disorder impacting the lung vasculature, resulting in increased pulmonary vascular resistance that leads to right ventricular dysfunction. Pulmonary hypertension comprises of 5 groups (PH group 1 to 5) where group 1 pulmonary arterial hypertension (PAH), results from alterations that directly affect the pulmonary arteries. Although PAH has a complex pathophysiology that is not completely understood, it is known to be a multifactorial disease that results from a combination of genetic, epigenetic and environmental factors, leading to a varied range of symptoms in PAH patients. PAH does not have a cure, its incidence and prevalence continue to increase every year, resulting in higher morbidity and mortality rates. In this review, we discuss the different pathologic mechanisms with a focus on epigenetic modifications and their roles in the development and progression of PAH. These modifications include DNA methylation, histone modifications, and microRNA dysregulation. Understanding these epigenetic modifications will improve our understanding of PAH and unveil novel therapeutic targets, thus steering research toward innovative treatment strategies.
Time to take HPV infection in colorectal cancer patients more seriously
Authors: Javadi Mahsa , Jalilian Shahram , Kanani Malek , Kia Vahid , Talaiezadeh Abdolhassan , Angali Kambiz Ahmadi , Ahmadi Mohammad Karimi Baba , Makvandi Manoochehr
Published: July 2024

Background

The association between viral infections and colorectal cancer (CRC) remains an enigma in cancer research. Certain types of Human Papillomaviruses (hr-HPVs), known for their oncogenic properties, have been observed in particular CRC biopsies, further adding to the enigma surrounding this association.

Materials and methods

This cross-sectional study was conducted on 40 confirmed cases of CRC adenocarcinoma. The presence and genotyping of HPV DNA in colorectal fresh tissue and urine samples was assessed using an HPV DNA hybridization kit. A subset of serum samples from both CRC cases and healthy volunteers was randomly chosen and subjected to western blot to investigate the presence of HPV16 E6/E7 oncoproteins carried by exosomes.

Results

It was observed that 26/40 HPV-positive CRC patients demonstrated 7 times more chance to develop colorectal cancer when compared to those 8/40 normal tissue (odds ratio [OR] = 7.4; confidence interval [CI] 95% = 0.483156–0.793718; p < 0.001). Of 26 HPV-positive CRC patients, 14 urine samples were also showed HPV DNA positivity (p = 0.013). High-risk HPV16 was the most prevalent genotype detected in both 24/40 tumor and 12/40 urine samples (p < 0.001). The tumor sample of a male was HPV45, while another male’s urine sample was HPV31. A female CRC patient had HPV83 in tumor and HPV56 in urine. Here, was the first detection of HPV83 in a CRC patient. Notably among 20 randomly selected serum exosome samples, one serum sample concurrently tested positive for both HPV16 E6 and E7 oncoproteins, and one sample tested positive for HPV16 E7 oncoprotein.

Conclusion

High risk HPV DNA detection in CRC urine samples supports non-invasive screening tools. Detection of HPV16 E6 and E7 oncoproteins in exosomes from serum samples shows potential for non-invasive diagnostics. HPV’s potential role in CRC development is also underscored. HPV vaccination should be implemented in low- and middle-income countries to prevent cancer.
A comprehensive analysis of digital health-focused Living Labs: innovative approaches to dementia
Authors: Figueiredo Teodora , Midão Luís , Carrilho Joana , Videira Henriques Diogo , Alves Sara , Duarte Natália , Bessa Maria João , Fidalgo José María , García Maria , Facal David , Felpete Alba , Filgueira Iván Rarís , Carlos Bernárdez Juan , Rodríguez Maxi , Costa Elísio
Published: July 2024

The increasing prevalence of dementia demands innovative solutions; however, existing technological products often lack tailored support for individuals living with this condition. The Living Lab approach, as a collaborative innovation method, holds promise in addressing this issue by actively involving end-users in the design and development of solutions adapted to their needs. Despite this potential, the approach still faces challenges due to its lack of recognition as a research methodology and its absence of tailored guidelines, particularly in dementia care, prompting inquiries into its effectiveness. This narrative review aims to fill this gap by identifying and analysing digital health Living Labs focusing on dementia solutions. Additionally, it proposes guidelines for enhancing their operations, ensuring sustainability, scalability, and greater impact on dementia care. Fifteen Living Labs were identified and analyzed. Based on trends, best practices, and literature, the guidelines emphasize user engagement, interdisciplinary collaboration, technological infrastructure, regulatory compliance, transparent innovation processes, impact measurement, sustainability, scalability, dissemination, and financial management. Implementing these guidelines can enhance the effectiveness and long-term impact of Living Labs in dementia care, fostering new collaborations globally.
Ensuring safety and efficacy in combination products: regulatory challenges and best practices
Authors: Gupta Deepak Kumar , Tiwari Akhilesh , Yadav Yashraj , Soni Pranay , Joshi Megha
Published: July 2024

Combination products, amalgamating drugs, biologics, and medical devices, have revolutionized the healthcare landscape with their potential for innovative therapies. However, the intersection of diverse components within these products presents a complex regulatory environment, demanding rigorous attention to safety and efficacy. This article delves into the intricate landscape of regulatory considerations, safety, and efficacy assessments pertaining to combination products—a category at the intersection of drugs, devices, and biologics. The regulatory framework, primarily governed by the U.S. Food and Drug Administration (FDA), necessitates a nuanced classification determining the regulatory pathway. Collaboration between diverse regulatory centers, such as the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH), underscores the integrated approach required for these innovative healthcare solutions. Safety considerations unravel the potential risks and adverse events associated with combining diverse components, emphasizing the need for robust risk assessment and mitigation strategies. The evaluation of efficacy involves sophisticated methodologies, clinical trials, and post-market surveillance, with recent advancements incorporating digital technologies. This comprehensive exploration aims to contribute to the evolving understanding and best practices in the regulatory and scientific realms, fostering collaboration and innovation in the development and assessment of combination products.
Establishment and application of quadruple fluorescence quantitative RT-PCR method for the identification of waterfowl astrovirus
Authors: Li Yang , Luo Juan , Zhang Fuyou , Shang Jiajing , Deng Chunran , Feng Yingjie , Meng Ge , Jiang Wenming , Yu Xiaohui , Liu Guanhui , Liu Hualei
Published: July 2024

Avian astrovirus can infect a variety of poultry species and cause viral diarrhea, with a wide epidemic range strong pathogenicity and a high incidence. Among them, Duck astrovirus 3(DAstV-3), Duck astrovirus 4(DAstV-4), Goose astrovirus 1(GoAstV-1) and Goose astrovirus 2(GoAstV-2) are four types of astroviruses newly discovered in waterfowl in recent years. In order to realize the rapid detection of these four kinds of waterfowl stellate viruses, specific primers and probes were engineered to target a highly conserved region of ORF1b gene of DAstV-3, GoAstV-1 and GoAstV-2 and the ORF2 gene of DAstV-4, and a quadruple fluorescence quantitative RT-PCR method was developed. The results indicate that the method established in this study has good specificity and no cross reactivity with other pathogens. This method can detect viruses with a minimum concentration of 1 × 101 copies/μL for DAstV-4, GoAstV-1 and GoAstV-2, respectively, while the minimum concentration for DAstV-3 is 1 × 102 copies/μL. Compared with the routinely used RT-PCR method, the limit of detection by the multiplex RT-PCR lower. Both intra- and inter-assay variability tests revealed excellent reproducibility. This method was then used to analyze 269 field samples, and the results were verified by genome sequencing. In conclusion, this study presents a sensitive, accurate, and specific method for detecting DAstV-3, DAstV-4, GoAstV-1, and GoAstV-2 in a single reaction, enabling the monitoring and differential diagnosis of these four types of waterfowl astroviruses.
Effects of exogenous copper on microbial metabolic function and carbon use efficiency of Panax notoginseng planting soil
Authors: Wang Tong , Wang Xu , Hadibi Tarik , Ma Xun , Yao Haoyi , Tang Zhenya , Fan Fangling , Huang Yizong
Published: July 2024

Soil copper (Cu) pollution is a serious environmental risk in the Panax notoginseng planting area. However, the effect of Cu on soil microbial metabolism and nutrient cycling in this area remains unknown. Therefore, Biolog ECO-plate and enzyme stoichiometry methods were utilized in this study to investigate the impact of exogenous Cu (control: 0 mg·kg−1; Cu100: 100 mg·kg−1; Cu400: 400 mg·kg−1; and Cu600: 600 mg·kg−1) on the metabolic function of soil microbial and nutrient limitation in the P. notoginseng soil. The results indicated that Cu100 significantly increased soil organic carbon (SOC), total phosphorus (TP), soil C:N, microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) 9.89%, 15.65%, 17.91%, 61.87%, and 90.56% higher than the control, respectively. Moreover, the carbon source utilization ratio of carbohydrates, amino acids, and amphiphilic compounds of Cu100 also increased by 7.16%, 25.47%, and 84.68%, respectively, compared with the control. The activities of β-1,4-glucosidase, cellobiohyrolase, leucine amino peptidase, β-1,4-N-acetylglucosaminidase, and phosphatase significantly decreased with increasing Cu concentration. Soil enzyme stoichiometry showed that all treatments were limited by nitrogen (vector angle < 45°; 19.045–22.081). Cu600 led to the lowest carbon limitation (1.798) and highest carbon use efficiency (CUE:0.267). The PLS-SEM model also showed that MBC, MBN, MBP, and microbial diversity positively affected carbon and nitrogen limitation (0.654 and 0.424). Soil carbon, nitrogen, phosphorus, stoichiometric ratio, MBC, MBN, and MBP positively affected CUE (0.527 and 0.589). The microbial diversity index significantly negatively affected CUE (−1.490). Multiple linear stepwise regression analyses showed that CUE was mainly influenced by MBC, AP, C:P, and LAP. Thus, P. notoginseng soil can benefit soil microbial carbon and nitrogen limitations at low Cu concentrations. Clarifying the metabolic activity and nutritional status of microorganisms under Cu stress can provide some theoretical basis for realizing China's comprehensive and effective management and control policies for environmental risks from metals by 2035.
Differential microRNA expression in the SH-SY5Y human cell model as potential biomarkers for Huntington’s disease
Authors: Belkozhayev Ayaz , Niyazova Raigul , Kamal Mohammad Amjad , Ivashchenko Anatoliy , Sharipov Kamalidin , Wilson Cornelia M.
Published: July 2024

Huntington’s disease (HD) is caused by an expansion of CAG trinucleotide repeat in the HTT gene; the exact pathogenesis of HD currently remains unclear. One of the promising directions in the study of HDs is to determine the molecular mechanism underlying the development and role of microRNAs (miRNAs). This study aimed to identify the profile of miRNAs in an HD human cell line model as diagnostic biomarkers for HD. To study HD, the human SH-SY5Y HD cell model is based on the expression of two different forms: pEGFP-Q23 and pEGFP-Q74 of HTT. The expression of Htt protein was confirmed using aggregation assays combined with immunofluorescence and Western blotting methods. miRNA levels were measured in SH-SY5Y neuronal cell model samples stably expressing Q23 and Q74 using the extraction-free HTG EdgeSeq protocol. A total of 2083 miRNAs were detected, and 354 (top 18 miRNAs) miRNAs were significantly differentially expressed (DE) (p < 0.05) in Q23 and Q74 cell lines. A majority of the miRNAs were downregulated in the HD cell model. Moreover, we revealed that six DE miRNAs target seven genes (ATN1, GEMIN4, EFNA5, CSMD2, CREBBP, ATXN1, and B3GNT) that play important roles in neurodegenerative disorders and showed significant expression differences in mutant Htt (Q74) when compared to wild-type Htt (Q23) using RT-qPCR (p < 0.05 and 0.01). We demonstrated the most important DE miRNA-mRNA profiles, interaction binding sites, and their related pathways in HD using experimental and bioinformatics methods. This will allow the development of novel diagnostic strategies and provide alternative therapeutic routes for treating HD.
Functionally linked amygdala and prefrontal cortical regions are innervated by both single and double projecting cholinergic neurons
Authors: Barabás Bence , Reéb Zsófia , Papp Orsolya I. , Hájos Norbert
Published: July 2024

Cholinergic cells have been proposed to innervate simultaneously those cortical areas that are mutually interconnected with each other. To test this hypothesis, we investigated the cholinergic innervation of functionally linked amygdala and prefrontal cortical regions. First, using tracing experiments, we determined that cholinergic cells located in distinct basal forebrain (BF) areas projected to the different nuclei of the basolateral amygdala (BLA). Specifically, cholinergic cells in the ventral pallidum/substantia innominata (VP/SI) innervated the basal nucleus (BA), while the horizontal limb of the diagonal band of Broca (HDB) projected to its basomedial nucleus (BMA). In addition, cholinergic neurons in these two BF areas gave rise to overlapping innervation in the medial prefrontal cortex (mPFC), yet their axons segregated in the dorsal and ventral regions of the PFC. Using retrograde-anterograde viral tracing, we demonstrated that a portion of mPFC-projecting cholinergic neurons also innervated the BLA, especially the BA. By injecting retrograde tracers into the mPFC and BA, we found that 28% of retrogradely labeled cholinergic cells were double labeled, which typically located in the VP/SI. In addition, we found that vesicular glutamate transporter type 3 (VGLUT3)-expressing neurons within the VP/SI were also cholinergic and projected to the mPFC and BA, implicating that a part of the cholinergic afferents may release glutamate. In contrast, we uncovered that GABA is unlikely to be a co-transmitter molecule in HDB and VP/SI cholinergic neurons in adult mice. The dual innervation strategy, i.e., the existence of cholinergic cell populations with single as well as simultaneous projections to the BLA and mPFC, provides the possibility for both synchronous and independent control of the operation in these cortical areas, a structural arrangement that may maximize computational support for functionally linked regions. The presence of VGLUT3 in a portion of cholinergic afferents suggests more complex functional effects of cholinergic system in cortical structures.
Extracellular vesicles released by LPS-stimulated spinal organotypic slices spread neuroinflammation into naïve slices through connexin43 hemichannel opening and astrocyte aberrant calcium dynamics
Authors: Memo Christian , Parisse Pietro , Amoriello Roberta , Pachetti Maria , Palandri Anabela , Casalis Loredana , Ballerini Clara , Ballerini Laura
Published: July 2024

Introduction

Neuroinflammation is a hallmark of multiple neurodegenerative diseases, shared by all pathological processes which primarily impact on neurons, including Central Nervous System (CNS) injuries. In reactive CNS, activated glia releases extracellular vesicles (EVs), nanosized membranous particles known to play a key role in intercellular communication. EVs mediate neuroinflammatory responses and might exacerbate tissue deterioration, ultimately influencing neurodegenerative disease progression.

Methods

We treated spinal cord organotypic slices with LPS, a ligand extensively used to induce sEVs release, to mimic mild inflammatory conditions. We combine atomic force microscopy (AFM), nanoparticle tracking (NTA) and western blot (WB) analysis to validate the isolation and characterisation of sEVs. We further use immunofluorescence and confocal microscopy with live calcium imaging by GCaMP6f reporter to compare glial reactivity to treatments with sEVs when isolated from resting and LPS treated organ slices.

Results

In our study, we focus on CNS released small EVs (sEVs) and their impact on the biology of inflammatory environment. We address sEVs local signalling within the CNS tissue, in particular their involvement in inflammation spreading mechanism(s). sEVs are harvested from mouse organotypic spinal cord cultures, an in vitro model which features 3D complexity and retains spinal cord resident cells. By confocal microscopy and live calcium imaging we monitor glial responses in naïve spinal slices when exposed to sEVs isolated from resting and LPS treated organ slices.

Discussion

We show that sEVs, only when released during LPS neuroinflammation, recruit naïve astrocytes in the neuroinflammation cycle and we propose that such recruitment be mediated by EVs hemichannel (HC) permeability.
Mapping the strain-stiffening behavior of the lung and lung cancer at microscale resolution using the crystal ribcage
Authors: LeBourdais Robert , Grifno Gabrielle N. , Banerji Rohin , Regan Kathryn , Suki Bela , Nia Hadi T.
Published: July 2024

Lung diseases such as cancer substantially alter the mechanical properties of the organ with direct impact on the development, progression, diagnosis, and treatment response of diseases. Despite significant interest in the lung’s material properties, measuring the stiffness of intact lungs at sub-alveolar resolution has not been possible. Recently, we developed the crystal ribcage to image functioning lungs at optical resolution while controlling physiological parameters such as air pressure. Here, we introduce a data-driven, multiscale network model that takes images of the lung at different distending pressures, acquired via the crystal ribcage, and produces corresponding absolute stiffness maps. Following validation, we report absolute stiffness maps of the functioning lung at microscale resolution in health and disease. For representative images of a healthy lung and a lung with primary cancer, we find that while the lung exhibits significant stiffness heterogeneity at the microscale, primary tumors introduce even greater heterogeneity into the lung’s microenvironment. Additionally, we observe that while the healthy alveoli exhibit strain-stiffening of ∼1.75 times, the tumor’s stiffness increases by a factor of six across the range of measured transpulmonary pressures. While the tumor stiffness is 1.4 times the lung stiffness at a transpulmonary pressure of three cmH2O, the tumor’s mean stiffness is nearly five times greater than that of the surrounding tissue at a transpulmonary pressure of 18 cmH2O. Finally, we report that the variance in both strain and stiffness increases with transpulmonary pressure in both the healthy and cancerous lungs. Our new method allows quantitative assessment of disease-induced stiffness changes in the alveoli with implications for mechanotransduction.
Review of chaos in hair-cell dynamics
Authors: Faber Justin , Bozovic Dolores
Published: July 2024

The remarkable signal-detection capabilities of the auditory and vestibular systems have been studied for decades. Much of the conceptual framework that arose from this research has suggested that these sensory systems rest on the verge of instability, near a Hopf bifurcation, in order to explain the detection specifications. However, this paradigm contains several unresolved issues. Critical systems are not robust to stochastic fluctuations or imprecise tuning of the system parameters. Further, a system poised at criticality exhibits a phenomenon known in dynamical systems theory as critical slowing down, where the response time diverges as the system approaches the critical point. An alternative description of these sensory systems is based on the notion of chaotic dynamics, where the instabilities inherent to the dynamics produce high temporal acuity and sensitivity to weak signals, even in the presence of noise. This alternative description resolves the issues that arise in the criticality picture. We review the conceptual framework and experimental evidence that supports the use of chaos for signal detection by these systems, and propose future validation experiments.
A new transfer entropy method for measuring directed connectivity from complex-valued fMRI data
Authors: Li Wei-Xing , Lin Qiu-Hua , Zhang Chao-Ying , Han Yue , Calhoun Vince D.
Published: July 2024

Background

Inferring directional connectivity of brain regions from functional magnetic resonance imaging (fMRI) data has been shown to provide additional insights into predicting mental disorders such as schizophrenia. However, existing research has focused on the magnitude data from complex-valued fMRI data without considering the informative phase data, thus ignoring potentially important information.

Methods

We propose a new complex-valued transfer entropy (CTE) method to measure causal links among brain regions in complex-valued fMRI data. We use the transfer entropy to model a general non-linear magnitude–magnitude and phase–phase directed connectivity and utilize partial transfer entropy to measure the complementary phase and magnitude effects on magnitude–phase and phase–magnitude causality. We also define the significance of the causality based on a statistical test and the shuffling strategy of the two complex-valued signals.

Results

Simulated results verified higher accuracy of CTE than four causal analysis methods, including a simplified complex-valued approach and three real-valued approaches. Using experimental fMRI data from schizophrenia and controls, CTE yields results consistent with previous findings but with more significant group differences. The proposed method detects new directed connectivity related to the right frontal parietal regions and achieves 10.2–20.9% higher SVM classification accuracy when inferring directed connectivity using anatomical automatic labeling (AAL) regions as features.

Conclusion

The proposed CTE provides a new general method for fully detecting highly predictive directed connectivity from complex-valued fMRI data, with magnitude-only fMRI data as a specific case.
Context-dependent hyperactivity in syngap1a and syngap1b zebrafish models of SYNGAP1-related disorder
Authors: Sumathipala Sureni H. , Khan Suha , Kozol Robert A. , Araki Yoichi , Syed Sheyum , Huganir Richard L. , Dallman Julia E.
Published: July 2024

Background and aims

SYNGAP1-related disorder (SYNGAP1-RD) is a prevalent genetic form of Autism Spectrum Disorder and Intellectual Disability (ASD/ID) and is caused by de novo or inherited mutations in one copy of the SYNGAP1 gene. In addition to ASD/ID, SYNGAP1 disorder is associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, and gastrointestinal distress. Mechanistic links between these diverse symptoms and SYNGAP1 variants remain obscure, therefore, our goal was to generate a zebrafish model in which this range of symptoms can be studied.

Methods

We used CRISPR/Cas9 to introduce frameshift mutations in the syngap1a and syngap1b zebrafish duplicates (syngap1ab) and validated these stable models for Syngap1 loss-of-function. Because SYNGAP1 is extensively spliced, we mapped splice variants to the two zebrafish syngap1a and b genes and identified mammalian-like isoforms. We then quantified locomotory behaviors in zebrafish syngap1ab larvae under three conditions that normally evoke different arousal states in wild-type larvae: aversive, high-arousal acoustic, medium-arousal dark, and low-arousal light stimuli.

Results

We show that CRISPR/Cas9 indels in zebrafish syngap1a and syngap1b produced loss-of-function alleles at RNA and protein levels. Our analyses of zebrafish Syngap1 isoforms showed that, as in mammals, zebrafish Syngap1 N- and C-termini are extensively spliced. We identified a zebrafish syngap1 α1-like variant that maps exclusively to the syngap1b gene. Quantifying locomotor behaviors showed that syngap1ab mutant larvae are hyperactive compared to wild-type but to differing degrees depending on the stimulus. Hyperactivity was most pronounced in low arousal settings, and hyperactivity was proportional to the number of mutant syngap1 alleles.

Limitations

Syngap1 loss-of-function mutations produce relatively subtle phenotypes in zebrafish compared to mammals. For example, while mouse Syngap1 homozygotes die at birth, zebrafish syngap1ab−/− survive to adulthood and are fertile, thus some aspects of symptoms in people with SYNGAP1-Related Disorder are not likely to be reflected in zebrafish.

Conclusion

Our data support mutations in zebrafish syngap1ab as causal for hyperactivity associated with elevated arousal that is especially pronounced in low-arousal environments.
Fresh Moringa Stenopetala leaves consumption and its determinants among pregnant women in southern Ethiopia
Authors: Derbo Zeritu Dewana , Debelew Gurmesa Tura
Published: July 2024

Background

A woman’s health and nutritional status has significant impact on her pregnancy situation. However, many pregnant women are undernourished. Moringa stenopetala is a plant consumed worldwide in various forms, and its consumption showed a reduction in the incidence of malnutrition. Although Moringa stenopetala is rich in essential macro- and micronutrients, there is little evidence on the proportion and determinants of fresh Moringa stenopetala leaf intake among pregnant women. The objective of this study was to fill this gap in the littérature and provide a baseline evidence for further research or intervention by investigation the proportion and determinants of fresh Moringa stenopetala leaf intake among pregnant women in the Gamo zone, south Ethiopian region.

Methods

A community-based cross-sectional study was conducted among 623 randomly selected pregnant women using a pre-tested and structured questionnaire via a face-to-face interview. The consumption pattern was assessed based on a self-reported dietary history over the last 30 days before data collection. Multivariable logistic regression model was fitted using STATA version 14. An adjusted odds ratio with a 95% confidence interval was reported to show an association between the dependent and independent variables with level of statistical significance at a p-value of <0.05.

Results

The proportion of fresh Moringa stenopetala leaves intake among pregnant women was 49.60% (95% CI: 45.67, 53.52%). The déterminants of fresh moringa leaf intake were being below 24 years old (AOR: 2.92; 95% CI: 1.51, 5.63), rural résidence (AOR: 1.97; 95% CI: 1.10, 3.50), antenatal care attendance (AOR: 2.08; 95% CI: 1.03, 4.21), history of contraceptive use (AOR: 1.88; 95% CI: 1.03, 3.55), and having a good knowledge about the importance of moringa Stenopetala (AOR: 9.76; 95% CI: 5.30, 17.95).

Conclusion

The study showed that almost half of the pregnant women consumed fresh Moringa stenopetala leaves. Women’s age, place of residence, prenatal care, history of contraceptive use, and knowledge of the benefits of Moringa Stenopetala were positively associated with the consumption of fresh Moringa Stenopetala leaves. Therefore, health authorities and stakeholders involved in maternal and child health need to target older women, and urban residents and promote the benefits of consumption by strengthening uptake of maternal health services and raising awareness about Moringa Stenopetela. Future studies involving large scale and longitudinal designs evidence are required to further validate the findings so that this nutritious diet can be promoted widely among pregnant women in the study area and Ethiopia at large.
The role of vitamin C in the prevention of pancreatic cancer: a systematic-review
Authors: Martínez-Domínguez Samuel J. , Laredo Viviana , García-Rayado Guillermo
Published: July 2024

Introduction and aim

The aim of this systematic review was to assess the role of vitamin C in the prevention of pancreatic cancer (PC).

Methods

A comprehensive literature search was performed in PubMed, Embase and Web of Science up to August 2023, to identify randomized controlled trials (RCT), cohort studies and mendelian randomization studies based on prospective databases assessing the role of vitamin C in PC prevention.

Results

A total of twelve studies including European and North-American participants were included: two RCT, three mendelian randomization (MR) studies and seven cohort studies. Both RCT showed high quality in Cochrane risk of bias tool. Only one cohort study had <7 points in Newcastle Ottawa Scale. Both RCT found no association between the intake of 500 mg/day of vitamin C and the incidence of PC. Only one prospective cohort study found an association between vitamin C serum levels and a lower incidence of PC. The remaining cohort studies and MR studies found no association between dietary/supplements intake of vitamin C or circulating vitamin C levels and the incidence of PC.

Conclusion

There is no supporting evidence that vitamin C prevents PC development. Future prospective quality studies including high-risk populations are needed.
Venetoclax in the treatment of secondary plasma cell leukemia with translocation t(11;14): a case report and literature review
Authors: Elsabah Hesham , Ghasoub Rola , El Omri Halima , Benkhadra Maria , Cherif Honar , Taha Ruba Y.
Published: July 2024

Introduction

Venetoclax is a BCL-2 inhibitor with proven efficacy in patients with multiple myeloma (MM) and translocation t(11;14). However, its role in plasma cell leukemia (PCL) remains unclear. Herein, we aimed to report a case of relapsed MM with secondary PCL and t(11;14) achieving complete (CR) and durable remission with venetoclax therapy.

Case presentation

A 52-year-old gentleman was diagnosed with MM-free light chain lambda (ISS III) in December 2016. He received induction therapy, followed by autologous stem cell transplant. (ASCT) in May 2017 and maintenance. A year later, the patient relapsed with secondary PCL. His cytogenetics analysis revealed t(11; 14). The patient failed salvage chemotherapy and was shifted to venetoclax with dexamethasone treatment. The patient attained complete remission (CR), which was maintained for two years and a half before he developed fatal COVID-19 pneumonia.

Conclusion

In comparison with the reported literature, this case report offers the latest compilation of the available evidence on the use of venetoclax in patients with PCL. Furthermore, our patient achieved CR for the longest reported durable response in literature thus far. Prospective clinical trials are needed to elucidate the optimal dosage, combination, and duration of treatment, ensuring better representation and generalizability of the findings. Meanwhile, venetoclax may be considered as a therapeutic option in patients with PCL t(11;14).
Brozopine ameliorates cognitive impairment via upregulating Nrf2, antioxidation and anti-inflammation activities
Authors: Fu Zhenzhen , Wang Xuening , Fan Yanan , Shang Dong , Zhang Jiahua , Xiao Tingting , Guo Jiajun , Wang Yi , Wang Zhiyu , Zhang Zixin , Jia Qingran , Zhu Jinpeng , Jahromi Alireza Behrouznam , Meng Yinuo , Gao Na , Chang Junbiao , Gao Yuan
Published: July 2024

Oxidative stress and inflammation are crucial factors contributing to the occurrence and development of vascular dementia (VD). In a previous study, we demonstrated that brozopine (BZP) is an anti-ischemic drug. In this study, a model of VD in rats with modified permanent bilateral common carotid artery occlusion (2-VO) was established in vivo, a model of cellular excitotoxicity/oxidative stress was established via L-glutamate-induced PC12 cell injury, a model of neuroinflammation was established in LPS-induced BV2 cells in vitro, and the ameliorative effect of BZP on cognitive impairment was assessed. BZP treatment improved memory deficit in VD rats through inhibiting Ca2+overload and the levels of oxidative stress, ferroptosis, and inflammatory markers (IL-1β, IL-6, and COX-2) in different brain regions. Additionally, we found that the levels of inflammatory markers in the plasma were also reduced in the VD rats. BZP was further found to have antioxidative stress, antiferroptosis (ferroptosis markers: GPX4, P53, and ACSL4), and antineuroinflammatory effects in PC12 and BV2 cells. Its mechanisms of action were found to be related to the activation of the Nrf2/TLR4/NF-κB pathway; the protective effect of BZP was partially inhibited after using Nrf2-specific inhibitors. Thus, BZP has therapeutic properties for the potential mitigation of cognitive impairment.
The irreversibility of microscopic motions
Authors: Wang Huai-Yu
Published: July 2024

People have long had a problem: the equations of motion that reflect the laws of physics are invariant under time inversion, while there always are irreversible processes for gases composed of microscopic particles. This article solves the problem. The point is that we should distinguish between the concepts of the equation of motion and concrete motion. We also need to distinguish between the concepts of time-inverse motion and reverse motion. The former is anticlockwise, which is a fictional motion, while the latter is clockwise. For the single-particle motions in classical mechanics and in quantum mechanics, we present mathematical expressions for time-inversion motion and reverse motion, respectively. We demonstrate that single-particle motion is irreversible. The definition of the reversibility of two-particle collisions is given. According to the definition, the two-particle collision as a microscopic motion process is irreversible. Consequently, for a gas consisting of a large number of particles colliding with each other, its movement should be irreversible, unless the condition of detailed balance is met. We provide a physical explanation for detailed balance, which does not concern the meaning of microscopic reversibility. The detailed balance means that after a pair of reciprocal collisions occur, the distribution function of the particles remains unchanged. Therefore, microscopic two-particle collision events are irreversible, but the statistical average of a large number of collision events makes it possible for the macroscopic process of a gas to be reversible. Conclusively, we clarify the microscopic mechanism of the irreversible process of gases.
Validation of formulae predicting stroke volume from arterial pressure: with particular emphasis on upright individuals in hot ambient conditions
Authors: Tsoutsoubi Lydia , Ioannou Leonidas G. , Ciuha Urša , Fisher Jason T. , Possnig Carmen , Simpson Lydia L. , Flouris Andreas D. , Lawley Justin , Mekjavic Igor B.
Published: July 2024

Introduction

During heatwaves, it is important to monitor workers’ cardiovascular health since 35% of those working in hot environments experience symptoms of heat strain. Wearable technology has been popularized for monitoring heart rate (HR) during recreational activities, but it can also be used to monitor occupational heat strain based on core and skin temperatures and HR. To our knowledge, no devices estimate the cardiovascular strain directly based on stroke volume (SV) or cardiac output (CO). In addition to the hardware, there are limitations regarding the lack of suitable algorithms that would provide such an index based on relevant physiological responses. The validation of the formulae already existing in literature was the principle aim of the present study.

Methods

We monitored the cardiovascular responses of our participants to a supine and 60° head-up tilt at the same time each day. During the test, we measured blood pressure derived by finger photoplethysmography, which also provided beat-by-beat measures of SV and CO. Afterwards, we compared the SV derived from the photoplethysmography with the one calculated with the different equations that already exist in literature.

Results

The evaluation of the formulae was based on comparing the error of prediction. This residual analysis compared the sum of the squared residuals generated by each formula using the same data set.

Conclusion

Our findings suggest that estimating SV with existing formulae is feasible, showing a good correlation and a relatively small bias. Thus, simply measuring workers’ blood pressure during breaks could estimate their cardiac strain.
Harmonizing the CBCL and SDQ ADHD scores by using linear equating, kernel equating, item response theory and machine learning methods
Authors: Jović Miljan , Haeri Maryam Amir , Whitehouse Andrew , van den Berg Stéphanie M.
Published: July 2024

Introduction

A problem that applied researchers and practitioners often face is the fact that different institutions within research consortia use different scales to evaluate the same construct which makes comparison of the results and pooling challenging. In order to meaningfully pool and compare the scores, the scales should be harmonized. The aim of this paper is to use different test equating methods to harmonize the ADHD scores from Child Behavior Checklist (CBCL) and Strengths and Difficulties Questionnaire (SDQ) and to see which method leads to the result.

Methods

Sample consists of 1551 parent reports of children aged 10-11.5 years from Raine study on both CBCL and SDQ (common persons design). We used linear equating, kernel equating, Item Response Theory (IRT), and the following machine learning methods: regression (linear and ordinal), random forest (regression and classification) and Support Vector Machine (regression and classification). Efficacy of the methods is operationalized in terms of the root-mean-square error (RMSE) of differences between predicted and observed scores in cross-validation.

Results and discussion

Results showed that with single group design, it is the best to use the methods that use item level information and that treat the outcome as interval measurement level (regression approach).
Resilience as a protective factor against depression in informal caregivers
Authors: Vázquez Fernando L. , Blanco Vanessa , Andrade Elena , Otero Patricia , Bueno Ana M. , Simón Miguel A. , Torres Ángela J.
Published: July 2024

Introduction

Although previous research has demonstrated that resilience can be protective against various mental health conditions such as depression, existing studies examining the relationship between resilience and depression have limitations. To our knowledge, the moderators of the relationship have not been examined. The aim of this study was to determine whether resilience acts as a protective factor against depression in informal caregivers and to examine potential moderators of the relationship between these variables.

Methods

In this cross-sectional study, 554 randomly selected informal caregivers participated (86.8% women, average age = 55.3 years). Major depressive episode, depressive symptomatology, resilience, positive environmental reward, negative automatic thoughts, self-efficacy, and personality were assessed.

Results

A total of 16.1% of informal caregivers met criteria for a depressive episode and 57.4% were at risk of developing depression. The average resilience score was 26.3 (SD = 7.6); 62.6% of participants were in the lower quartile of the resilience scale. The gender of the informal caregiver and self-efficacy acted as moderating variables in the relationship between resilience and depression. The impact of resilience on depressive symptoms was more pronounced in female informal caregivers, and increased as self-efficacy increased.

Discussion

Based on these findings, programs aimed at preventing depression in informal caregivers should focus on promoting resilience, especially in women, and introduce strategies to enhance self-efficacy to increase their impact.
Examination of self patterns: framing an alternative phenomenological interview for use in mental health research and clinical practice
Authors: Daly Anya , Ritunnano Rosa , Gallagher Shaun , Kirmayer Laurence J. , Van Dam Nicholas , Kleinman Joshua
Published: July 2024

Mental disorders are increasingly understood as involving complex alterations of self that emerge from dynamical interactions of constituent elements, including cognitive, bodily, affective, social, narrative, cultural and normative aspects and processes. An account of self that supports this view is the pattern theory of self (PTS). The PTS is a non-reductive account of the self, consistent with both embodied-enactive cognition and phenomenological psychopathology; it foregrounds the multi-dimensionality of subjects, stressing situated embodiment and intersubjective processes in the formation of the self-pattern. Indications in the literature already demonstrate the viability of the PTS for formulating an alternative methodology to better understand the lived experience of those suffering mental disorders and to guide mental health research more generally. This article develops a flexible methodological framework that front-loads the self-pattern into a minimally structured phenomenological interview. We call this framework ‘Examination of Self Patterns’ (ESP). The ESP is unconstrained by internalist or externalist assumptions about mind and is flexibly guided by person-specific interpretations rather than pre-determined diagnostic categories. We suggest this approach is advantageous for tackling the inherent complexity of mental health, the clinical protocols and the requirements of research.