bluuebunny/crossref_metadata_2025 huggingface dataset:
Subjective Well-Being, Health and Socio-Demographic Factors Related to COVID-19 Vaccination: A Repeated Cross-Sectional Sample Survey Study from 2021–2022 in Urban Pakistan
Authors: Shams Khadija , Kadow Alexander
Published: August 2023

Background: Containing the spread of the COVID-19 rests on many people willing to get vaccinated. At the same time, it is important to recognize the various socio-demographic factors associated with COVID-19 vaccination. This paper aims to identify socio-demographic and health factors related to the COVID-19 vaccine and its impact on subjective well-being in urban Pakistan. Methods: Pooled cross-sectional sample surveys collected in 2021 and 2022 (n = 4500 households) via a questionnaire provided to household’s heads. In each wave, data were collected using the same methodology, sample size and sampling techniques (proportional stratified random sampling). An ordered probit regression model was used to identify the various socio-demographic and health factors related to the COVID-19 vaccine and its impact on subjective well-being. Sample weights were applied to all the regression analyses to improve population generalizability. Results and conclusion: Besides socio-demographic factors such as being healthy, educated and richer, coronavirus vaccination plays a positive and significant role in overall subjective well-being. However, vaccination has a smaller effect on men or older populations compared to women or younger populations in terms of their subjective well-being. Moreover, as expected, the vaccination has the strongest positive effect on the healthy population and its subjective well-being.
Assessing the Efficacy of a Brief Universal Family Skills Programme on Violence and Substance-Use Indicators in Youth in Trentino and Parma, Italy: Study Protocol for a Multi-Centre, Non-Blinded, Cluster-Randomised Controlled Trial (cRCT) of Family UNited
Authors: Haar Karin , El-Khani Aala , Lodi Riccardo , Molin Valentina , Pelosi Annalisa , Yassine Ali , Campello Giovanna , Maalouf Wadih
Published: August 2023

Homes in which families are experiencing stressful and challenging circumstances can foster a social space that engenders violent behaviours in parents, inadequate childcare, and the exposure of children to criminal and antisocial behaviours at an early age in addition to many other negative social and health consequences throughout their development. Family Skills Training offers a combination of parenting knowledge, skill building, competency enhancement, and support to strengthen family protective factors, such as communication, trust, problem-solving skills, and conflict resolution. Through over a decade-long experience piloting evidence-based family skills packages globally, we developed a universal open-source family skills package, “Family UNited” (FU), designed for families with children aged 8 to 15 years living in low- and middle-income countries (LMIC). The current study aims to explore the efficacy, fidelity, and acceptability of FU in Trentino and Parma, Italy. We plan to conduct a multi-site, non-blinded, two-armed, cluster-randomised controlled trial to assess efficacy in 160 families: the intervention group receiving FU and the waitlist/control group only receiving FU after the completion of all data collection points. We will prospectively collect outcome data, assessing changes in parenting skills and family adjustment in caregivers, children’s behaviour, resilience capacities, and attitudes towards peer violence. To assess programme delivery, fidelity, feasibility, and acceptability we will include an embedded process evaluation. This study aims to evaluate the improvement in parenting skills, child well-being, and family mental health after participation in FU, compared to no intervention. Even though this trial is to be conducted in a high-income country, such results complement the existing piloting experience in LMIC. with impact-related measures encouraging the adoption of such approaches globally and beyond the EU borders.
Interaction of L1CAM with LC3 Is Required for L1-Dependent Neurite Outgrowth and Neuronal Survival
Authors: Loers Gabriele , Kleene Ralf , Granato Viviana , Bork Ute , Schachner Melitta
Published: August 2023

The neural cell adhesion molecule L1 (also called L1CAM or CD171) functions not only in cell migration, but also in cell survival, differentiation, myelination, neurite outgrowth, and signaling during nervous system development and in adults. The proteolytic cleavage of L1 in its extracellular domain generates soluble fragments which are shed into the extracellular space and transmembrane fragments that are internalized into the cell and transported to various organelles to regulate cellular functions. To identify novel intracellular interaction partners of L1, we searched for protein–protein interaction motifs and found two potential microtubule-associated protein 1 light-chain 3 (LC3)-interacting region (LIR) motifs within L1, one in its extracellular domain and one in its intracellular domain. By ELISA, immunoprecipitation, and proximity ligation assay using L1 mutant mice lacking the 70 kDa L1 fragment (L1-70), we showed that L1-70 interacts with LC3 via the extracellular LIR motif in the fourth fibronectin type III domain, but not by the motif in the intracellular domain. The disruption of the L1-LC3 interaction reduces L1-mediated neurite outgrowth and neuronal survival.
Genome-Wide Comparison and Functional Characterization of HMGR Gene Family Associated with Shikonin Biosynthesis in Lithospermum erythrorhizon
Authors: Wang Xuan , Wang Changyi , Yang Minkai , Jie Wencai , Fazal Aliya , Fu Jiangyan , Yin Tongming , Cai Jinfeng , Liu Bao , Lu Guihua , Lin Hongyan , Han Hongwei , Wen Zhongling , Qi Jinliang , Yang Yonghua
Published: August 2023

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), as the rate-limiting enzyme in the mevalonate pathway, is essential for the biosynthesis of shikonin in Lithospermum erythrorhizon. However, in the absence of sufficient data, the principles of a genome-wide in-depth evolutionary exploration of HMGR family members in plants, as well as key members related to shikonin biosynthesis, remain unidentified. In this study, 124 HMGRs were identified and characterized from 36 representative plants, including L. erythrorhizon. Vascular plants were found to have more HMGR family genes than nonvascular plants. The phylogenetic tree revealed that during lineage and species diversification, the HMGRs evolved independently and intronless LerHMGRs emerged from multi-intron HMGR in land plants. Among them, Pinus tabuliformis and L. erythrorhizon had the most HMGR gene duplications, with 11 LerHMGRs most likely expanded through WGD/segmental and tandem duplications. In seedling roots and M9 cultured cells/hairy roots, where shikonin biosynthesis occurs, LerHMGR1 and LerHMGR2 were expressed significantly more than other genes. The enzymatic activities of LerHMGR1 and LerHMGR2 further supported their roles in catalyzing the conversion of HMG-CoA to mevalonate. Our findings provide insight into the molecular evolutionary properties and function of the HMGR family in plants and a basis for the genetic improvement of efficiently produced secondary metabolites in L. erythrorhizon.
Role of Cx43 in iPSC-CM Damage Induced by Microwave Radiation
Authors: Yin Yue , Xu Xinping , Li Dayan , Yao Binwei , Wang Haoyu , Zhao Li , Wang Hui , Dong Ji , Zhang Jing , Peng Ruiyun
Published: August 2023

The heart is one of the major organs affected by microwave radiation, and these effects have been extensively studied. Previous studies have shown that microwave-radiation-induced heart injury might be related to the abnormal expression and distribution of Cx43. In order to make the research model closer to humans, we used iPSC-CMs as the cell injury model to investigate the biological effect and mechanism of iPSC-CM injury after microwave radiation. To model the damage, iPSC-CMs were separated into four groups and exposed to single or composite S-band (2.856 GHz) and X-band (9.375 GHz) microwave radiation sources with an average power density of 30 mW/cm2. After that, FCM was used to detect cell activity, and ELISA was used to detect the contents of myocardial enzymes and injury markers in the culture medium, and it was discovered that cell activity decreased and the contents increased after radiation. TEM and SEM showed that the ultrastructure of the cell membrane, mitochondria, and ID was damaged. Mitochondrial function was aberrant, and glycolytic capacity decreased after exposure. The electrical conduction function of iPSC-CM was abnormal; the conduction velocity was decreased, and the pulsation amplitude was reduced. Wb, qRT-PCR, and IF detections showed that the expression of Cx43 was decreased and the distribution of Cx43 at the gap junction was disordered. Single or composite exposure to S- and X-band microwave radiation caused damage to the structure and function of iPSC-CMs, primarily affecting the cell membrane, mitochondria, and ID. The composite exposure group was more severely harmed than the single exposure group. These abnormalities in structure and function were related to the decreased expression and disordered distribution of Cx43.
Proteomic and Mutant Analysis of Hydrogenase Maturation Protein Gene hypE in Symbiotic Nitrogen Fixation of Mesorhizobium huakuii
Authors: Long Songhua , Su Min , Chen Xiaohong , Hu Aiqi , Yu Fuyan , Zou Qian , Cheng Guojun
Published: August 2023

Hydrogenases catalyze the simple yet important redox reaction between protons and electrons and H2, thus mediating symbiotic interactions. The contribution of hydrogenase to this symbiosis and anti-oxidative damage was investigated using the M. huakuii hypE (encoding hydrogenase maturation protein) mutant. The hypE mutant grew a little faster than its parental 7653R and displayed decreased antioxidative capacity under H2O2-induced oxidative damage. Real-time quantitative PCR showed that hypE gene expression is significantly up-regulated in all the detected stages of nodule development. Although the hypE mutant can form nodules, the symbiotic ability was severely impaired, which led to an abnormal nodulation phenotype coupled to a 47% reduction in nitrogen fixation capacity. This phenotype was linked to the formation of smaller abnormal nodules containing disintegrating and prematurely senescent bacteroids. Proteomics analysis allowed a total of ninety differentially expressed proteins (fold change > 1.5 or <0.67, p < 0.05) to be identified. Of these proteins, 21 are related to stress response and virulence, 21 are involved in transporter activity, and 18 are involved in energy and nitrogen metabolism. Overall, the HypE protein is essential for symbiotic nitrogen fixation, playing independent roles in supplying energy and electrons, in bacterial detoxification, and in the control of bacteroid differentiation and senescence.
Possible Therapies for Hepatocellular Carcinoma—Preparing for the Modern War with the Insidious Enemy
Authors: Wasilewicz Michał P.
Published: August 2023

Hepatocellular carcinoma (HCC) accounts for 7% of all malignancies and about 90% of all primary liver malignancies, making it the most common type of malignant liver neoplasm [...]
Production of Tissue-Engineered Skin Substitutes for Clinical Applications: Elimination of Serum
Authors: Doucet Emilie J. , Cortez Ghio Sergio , Barbier Martin A. , Savard Étienne , Magne Brice , Safoine Meryem , Larouche Danielle , Fradette Julie , Germain Lucie
Published: August 2023

Tissue-engineered skin substitutes (TESs) are used as a treatment for severe burn injuries. Their production requires culturing both keratinocytes and fibroblasts. The methods to grow these cells have evolved over the years, but bovine serum is still commonly used in the culture medium. Because of the drawbacks associated with the use of serum, it would be advantageous to use serum-free media for the production of TESs. In a previous study, we developed a serum-free medium (Surge SFM) for the culture of keratinocytes. Herein, we tested the use of this medium, together with a commercially available serum-free medium for fibroblasts (Prime XV), to produce serum-free TESs. Our results show that serum-free TESs are macroscopically and histologically similar to skin substitutes produced with conventional serum-containing media. TESs produced with either culture media expressed keratin 14, Ki-67, transglutaminase 1, filaggrin, type I and IV collagen, and fibronectin comparably. Mechanical properties, such as contraction and tensile strength, were comparable between TESs cultured with and without serum. Serum-free TESs were also successfully grafted onto athymic mice for a six-month period. In conclusion, Surge SFM and Prime XV serum-free media could be used to produce high quality clinical-grade skin substitutes.
Six Functions of Respiration: Isn’t It Time to Take Control over ROS Production in Mitochondria, and Aging Along with It?
Authors: Skulachev Vladimir P. , Vyssokikh Mikhail Yu. , Chernyak Boris V. , Mulkidjanian Armen Y. , Skulachev Maxim V. , Shilovsky Gregory A. , Lyamzaev Konstantin G. , Borisov Vitaliy B. , Severin Fedor F. , Sadovnichii Victor A.
Published: August 2023

Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function #6, which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation. Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.
Management and Mitigation of Vibriosis in Aquaculture: Nanoparticles as Promising Alternatives
Authors: Kah Sem Nuan Anong Densaad , Abd Gani Shafinaz , Chong Chou Min , Natrah Ikhsan , Shamsi Suhaili
Published: August 2023

Vibriosis is one of the most common diseases in marine aquaculture, caused by bacteria belonging to the genus Vibrio, that has been affecting many species of economically significant aquatic organisms around the world. The prevention of vibriosis in aquaculture is difficult, and the various treatments for vibriosis have their limitations. Therefore, there is an imperative need to find new alternatives. This review is based on the studies on vibriosis, specifically on the various treatments and their limitations, as well as the application of nanoparticles in aquaculture. One of the promising nanoparticles is graphene oxide (GO), which has been used in various applications, particularly in biological applications such as biosensors, drug delivery, and potential treatment for infectious diseases. GO has been shown to have anti-bacterial properties against both Gram-positive and Gram-negative bacteria, but no research has been published that emphasizes its impact on Vibrio spp. The review aims to explore the potential use of GO for treatment against vibriosis.
Crosstalk of Mast Cells and Natural Killer Cells with Neurons in Chemotherapy-Induced Peripheral Neuropathy
Authors: Yun Hyun Don , Goel Yugal , Gupta Kalpna
Published: August 2023

Chemotherapy-induced peripheral neuropathy (CIPN) is a major comorbidity of cancer. Multiple clinical interventions have been studied to effectively treat CIPN, but the results have been disappointing, with no or little efficacy. Hence, understanding the pathophysiology of CIPN is critical to improving the quality of life and clinical outcomes of cancer patients. Although various mechanisms of CIPN have been described in neuropathic anti-cancer agents, the neuroinflammatory process involving cytotoxic/proinflammatory immune cells remains underexamined. While mast cells (MCs) and natural killer (NK) cells are the key innate immune compartments implicated in the pathogenesis of peripheral neuropathy, their role in CIPN has remained under-appreciated. Moreover, the biology of proinflammatory cytokines associated with MCs and NK cells in CIPN is particularly under-evaluated. In this review, we will focus on the interactions between MCs, NK cells, and neuronal structure and their communications via proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in peripheral neuropathy in association with tumor immunology. This review will help lay the foundation to investigate MCs, NK cells, and cytokines to advance future therapeutic strategies for CIPN.
DHEA Induces Sex-Associated Differential Patterns in Cytokine and Antibody Levels in Mice Infected with Plasmodium berghei ANKA
Authors: Buendía-González Fidel Orlando , Cervantes-Candelas Luis Antonio , Aguilar-Castro Jesús , Fernández-Rivera Omar , Nolasco-Pérez Teresita de Jesús , López-Padilla Monserrat Sofía , Chavira-Ramírez David Roberto , Cervantes-Sandoval Armando , Legorreta-Herrera Martha
Published: August 2023

Malaria is the most lethal parasitic disease worldwide; the severity of symptoms and mortality are higher in men than in women, exhibiting an evident sexual dimorphism in the immune response; therefore, the contribution of 17β-estradiol and testosterone to this phenomenon has been studied. Both hormones differentially affect several aspects of innate and adaptive immunity. Dehydroepiandrosterone (DHEA) is the precursor of both hormones and is the sexual steroid in higher concentrations in humans, with immunomodulatory properties in different parasitic diseases; however, the involvement of DHEA in this sexual dimorphism has not been studied. In the case of malaria, the only information is that higher levels of DHEA are associated with reduced Plasmodium falciparum parasitemia. Therefore, this work aims to analyze the DHEA contribution to the sexual dimorphism of the immune response in malaria. We assessed the effect of modifying the concentration of DHEA on parasitemia, the number of immune cells in the spleen, cytokines, and antibody levels in plasma of CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). DHEA differentially affected the immune response in males and females: it decreased IFN-γ, IL-2 and IL-4 concentrations only in females, whereas in gonadectomized males, it increased IgG2a and IgG3 antibodies. The results presented here show that DHEA modulates the immune response against Plasmodium differently in each sex, which helps to explain the sexual dimorphism present in malaria.
Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice
Authors: Fitz Nicholas F. , Sahu Amrita , Lu Yi , Ambrosio Fabrisia , Lefterov Iliya , Koldamova Radosveta
Published: August 2023

We have previously demonstrated that circulating extracellular vesicles (EVs) are essential to the beneficial effect of young serum on the skeletal muscle regenerative cascade. Here, we show that infusions of young serum significantly improve age-associated memory deficits, and that these effects are abolished after serum depletion of EVs. RNA-seq analysis of the choroid plexus demonstrates EV-mediated effects on genes involved in barrier function and trans-barrier transport. Comparing the differentially expressed genes to recently published chronological aging clock genes reveals a reversal of transcriptomic aging in the choroid plexus. Following young serum treatment, the hippocampal transcriptome demonstrates significant upregulation of the anti-aging gene Klotho, along with an abrogated effect after EV depletion. Transcriptomic profiling of Klotho knockout and heterozygous mice shows the downregulation of genes associated with transport, exocytosis, and lipid transport, while upregulated genes are associated with activated microglia. The results of our study indicate the significance of EVs as vehicles to deliver signals from the periphery to the brain and the importance of Klotho in maintaining brain homeostasis.
The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies
Authors: Vila-Pueyo Marta , Gliga Otilia , Gallardo Víctor José , Pozo-Rosich Patricia
Published: August 2023

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine.
Genome-Wide Identification and Expression Analysis of ANS Family in Strawberry Fruits at Different Coloring Stages
Authors: Feng Yongqing , Yang Shangwen , Li Wenfang , Mao Juan , Chen Baihong , Ma Zonghuan
Published: August 2023

To elucidate the structural characteristics, phylogeny and biological function of anthocyanin synthase (ANS) and its role in anthocyanin synthesis, members of the strawberry ANS gene family were obtained by whole genome retrieval, and their bioinformatic analysis and expression analysis at different developmental stages of fruit were performed. The results showed that the strawberry ANS family consisted of 141 members distributed on 7 chromosomes and could be divided into 4 subfamilies. Secondary structure prediction showed that the members of this family were mainly composed of random curls and α-helices, and were mainly located in chloroplasts, cytoplasm, nuclei and cytoskeletons. The promoter region of the FvANS gene family contains light-responsive elements, abiotic stress responsive elements and hormone responsive elements, etc. Intraspecific collinearity analysis revealed 10 pairs of FvANS genes, and interspecific collinearity analysis revealed more relationships between strawberries and apples, grapes and Arabidopsis, but fewer between strawberries and rice. Chip data analysis showed that FvANS15, FvANS41, FvANS47, FvANS48, FvANS49, FvANS67, FvANS114 and FvANS132 were higher in seed coat tissues and endosperm. FvANS16, FvANS85, FvANS90 and FvANS102 were higher in internal and fleshy tissues. Quantitative real-time PCR (qRT-PCR) showed that the ANS gene was expressed throughout the fruit coloring process. The expression levels of most genes were highest in the 50% coloring stage (S3), such as FvANS16, FvANS19, FvANS31, FvANS43, FvANS73, FvANS78 and FvANS91. The expression levels of FvANS52 were the highest in the green fruit stage (S1), and FvANS39 and FvANS109 were the highest in the 20% coloring stage (S2). These results indicate that different members of the FvANS gene family play a role in different pigmentation stages, with most genes playing a role in the expression level of the rapid accumulation of fruit coloring. This study lays a foundation for further study on the function of ANS gene family.
IL-21/IL-21R Promotes the Pro-Inflammatory Effects of Macrophages during C. muridarum Respiratory Infection
Authors: Yang Shuaini , Zeng Jiajia , Hao Wenlian , Sun Ruoyuan , Tuo Yuqing , Tan Lu , Zhang Hong , Liu Ran , Bai Hong
Published: August 2023

Interleukin-21 and its receptors (IL-21/IL-21R) aggravate chlamydial lung infection, while macrophages (Mφ) are one of the main cells infected by chlamydia and the main source of inflammatory cytokines. Therefore, it is particularly important to study whether IL-21/IL-21R aggravates chlamydia respiratory infection by regulating Mφ. Combined with bioinformatics analysis, we established an IL-21R-deficient (IL-21R−/−) mouse model of Chlamydia muridarum (C. muridarum) respiratory tract infection in vivo, studied C. muridarum-stimulated RAW264.7 by the addition of rmIL-21 in vitro, and conducted adoptive transfer experiments to clarify the association between IL-21/IL-21R and Mφ. IL-21R−/− mice showed lower infiltration of pulmonary total Mφ, alveolar macrophages, and interstitial macrophages compared with WT mice following infection. Transcriptomic analysis suggested that M1-related genes are downregulated in IL-21R−/− mice and that IL-21R deficiency affects the Mφ-mediated inflammatory response during C. muridarum infection. In vivo experiments verified that in IL-21R−/− mice, pulmonary M1-type CD80+, CD86+, MHC II+, TNFα+, and iNOS+ Mφ decreased, while there were no differences in M2-type CD206+, TGF-β+, IL-10+ and ARG1+ Mφ. In vitro, administration of rmIL-21 to C. muridarum-stimulated RAW264.7 cells promoted the levels of iNOS-NO and the expression of IL-12p40 and TNFα, but had no effect on TGFβ or IL-10. Further, adoptive transfer of M1-like bone marrow-derived macrophages derived from IL-21R−/− mice, unlike those from WT mice, effectively protected the recipients against C. muridarum infection and induced relieved pulmonary pathology. These findings help in understanding the mechanism by which IL-21/IL-21R exacerbates chlamydia respiratory infection by promoting the proinflammatory effect of Mφ.
Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility
Authors: Sánchez-Jasso Diego Eduardo , López-Guzmán Sergio Federico , Bermúdez-Cruz Rosa Maria , Oviedo Norma
Published: August 2023

Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of specialized genes in meiosis, among other specific functions for the formation of the spermatozoon. The transcription factor cAMP-response element modulator (CREM) is a key modulator that triggers the differentiation of the germ cell into the spermatozoon through the modification of gene expression. CREM has multiple repressor and activator isoforms whose expression is tissue-cell-type specific and tightly regulated by various factors at the transcriptional, post-transcriptional and post-translational level. The activator isoform CREMτ controls the expression of several relevant genes in post-meiotic stages of spermatogenesis. In addition, exposure to xenobiotics negatively affects CREMτ expression, which is linked to male infertility. On the other hand, antioxidants could have a positive effect on CREMτ expression and improve sperm parameters in idiopathically infertile men. Therefore, CREM expression could be used as a biomarker to detect and even counteract male infertility. This review examines the importance of CREM as a transcription factor for sperm production and its relevance in male fertility, infertility and the response to environmental xenobiotics that may affect CREMτ expression and the downstream regulation that alters male fertility. Also, some health disorders in which CREM expression is altered are discussed.
Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells
Authors: Soejima Yoshiaki , Iwata Nahoko , Nishioka Ran , Honda Mako , Nakano Yasuhiro , Yamamoto Koichiro , Suyama Atsuhito , Otsuka Fumio
Published: August 2023

Orexins are neuropeptides that play important roles in sleep-wake regulation and food intake in the central nervous system, but their receptors are also expressed in peripheral tissues, including the endocrine system. In the present study, we investigated the functions of orexin in adrenal steroidogenesis using human adrenocortical H295R cells by focusing on its interaction with adrenocortical bone morphogenetic proteins (BMPs) that induce adrenocortical steroidogenesis. Treatment with orexin A increased the mRNA levels of steroidogenic enzymes including StAR, CYP11B2, CYP17, and HSD3B1, and these effects of orexin A were further enhanced in the presence of forskolin. Interestingly, orexin A treatment suppressed the BMP-receptor signaling detected by Smad1/5/9 phosphorylation and Id-1 expression through upregulation of inhibitory Smad7. Orexin A also suppressed endogenous BMP-6 expression but increased the expression of the type-II receptor of ActRII in H295R cells. Moreover, treatment with BMP-6 downregulated the mRNA level of OX1R, but not that of OX2R, expressed in H295R cells. In conclusion, the results indicate that both orexin and BMP-6 accelerate adrenocortical steroidogenesis in human adrenocortical cells; both pathways mutually inhibit each other, thereby leading to a fine-tuning of adrenocortical steroidogenesis.
miR-143-3p Promotes Ovarian Granulosa Cell Senescence and Inhibits Estradiol Synthesis by Targeting UBE2E3 and LHCGR
Authors: Deng Jingxian , Tang Yan , Li Lu , Huang Rufei , Wang Zhaoyang , Ye Tao , Xiao Ziyan , Hu Meirong , Wei Siying , Wang Yuxin , Yang Yan , Huang Yadong
Published: August 2023

The ovary is a highly susceptible organ to senescence, and granulosa cells (GCs) have a crucial role in oocyte development promotion and overall ovarian function maintenance. As age advances, GCs apoptosis and dysfunction escalate, leading to ovarian aging. However, the molecular mechanisms underpinning ovarian aging remain poorly understood. In this study, we observed a correlation between the age-related decline of fertility and elevated expression levels of miR-143-3p in female mice. Moreover, miR-143-3p was highly expressed in senescent ovarian GCs. The overexpression of miR-143-3p in GCs not only hindered their proliferation and induced senescence-associated secretory phenotype (SASP) but also impeded steroid hormone synthesis by targeting ubiquitin-conjugating enzyme E2 E3 (Ube2e3) and luteinizing hormone and human chorionic gonadotropin receptor (Lhcgr). These findings suggest that miR-143-3p plays a substantial role in senescence and steroid hormone synthesis in GCs, indicating its potential as a therapeutic target for interventions in the ovarian aging process.
Classification of Promoter Sequences from Human Genome
Authors: Zaytsev Konstantin , Fedorov Alexey , Korotkov Eugene
Published: August 2023

We have developed a new method for promoter sequence classification based on a genetic algorithm and the MAHDS sequence alignment method. We have created four classes of human promoters, combining 17,310 sequences out of the 29,598 present in the EPD database. We searched the human genome for potential promoter sequences (PPSs) using dynamic programming and position weight matrices representing each of the promoter sequence classes. A total of 3,065,317 potential promoter sequences were found. Only 1,241,206 of them were located in unannotated parts of the human genome. Every other PPS found intersected with either true promoters, transposable elements, or interspersed repeats. We found a strong intersection between PPSs and Alu elements as well as transcript start sites. The number of false positive PPSs is estimated to be 3 × 10−8 per nucleotide, which is several orders of magnitude lower than for any other promoter prediction method. The developed method can be used to search for PPSs in various eukaryotic genomes.
Difunctional Magnetic Nanoparticles Employed in Immunochromatographic Assay for Rapid and Quantitative Detection of Carcinoembryonic Antigen
Authors: Hu Yalin , Lu Xin , Shen Liyue , Dong Jiahui , Liang Zhanwei , Xie Jie , Peng Tao , Yu Xiaoping , Dai Xinhua
Published: August 2023

Immunochromatographic assay (ICA) plays an important role in in vitro diagnostics because of its simpleness, convenience, fastness, sensitivity, accuracy, and low cost. The employment of magnetic nanoparticles (MNPs), possessing both excellent optical properties and magnetic separation functions, can effectively promote the performances of ICA. In this study, an ICA based on MNPs (MNP–ICA) has been successfully developed for the sensitive detection of carcinoembryonic antigen (CEA). The magnetic probes were prepared by covalently conjugating carboxylated MNPs with the specific monoclonal antibody against CEA, which were not only employed to enrich and extract CEA from serum samples under an external magnetic field but also used as a signal output with its inherent optical property. Under the optimal parameters, the limit of detection (LOD) for qualitative detection with naked eyes was 1.0 ng/mL, and the quantitative detection could be realized with the help of a portable optical reader, indicating that the ratio of optical signal intensity correlated well with CEA concentration ranging from 1.0 ng/mL to 64.0 ng/mL (R2 = 0.9997). Additionally, method comparison demonstrated that the magnetic probes were beneficial for sensitivity improvement due to the matrix effect reduction after magnetic separation, and the MNP–ICA is eight times higher sensitive than ICA based on colloidal gold nanoparticles. The developed MNP–ICA will provide sensitive, convenient, and efficient technical support for biomarkers rapid screening in cancer diagnosis and prognosis.
Neuroinflammation Profiling of Brain Cytokines Following Repeated Blast Exposure
Authors: Heyburn Lanier , Batuure Andrew , Wilder Donna , Long Joseph , Sajja Venkatasivasai Sujith
Published: August 2023

Due to use of explosive devices and heavy weapons systems in modern conflicts, the effect of BW on the brain and body is of increasing concern. These exposures have been commonly linked with neurodegenerative diseases and psychiatric disorders in veteran populations. A likely neurobiological link between exposure to blasts and the development of neurobehavioral disorders, such as depression and PTSD, could be neuroinflammation triggered by the blast wave. In this study, we exposed rats to single or repeated BW (up to four exposures—one per day) at varied intensities (13, 16, and 19 psi) to mimic the types of blast exposures that service members may experience in training and combat. We then measured a panel of neuroinflammatory markers in the brain tissue with a multiplex cytokine/chemokine assay to understand the pathophysiological process(es) associated with single and repeated blast exposures. We found that single and repeated blast exposures promoted neuroinflammatory changes in the brain that are similar to those characterized in several neurological disorders; these effects were most robust after 13 and 16 psi single and repeated blast exposures, and they exceeded those recorded after 19 psi repeated blast exposures. Tumor necrosis factor-alpha and IL-10 were changed by 13 and 16 psi single and repeated blast exposures. In conclusion, based upon the growing prominence of negative psychological health outcomes in veterans and soldiers with a history of blast exposures, identifying the molecular etiology of these disorders, such as blast-induced neuroinflammation, is necessary for rationally establishing countermeasures and treatment regimens.
Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neuron Functions
Authors: Martella Giuseppina
Published: August 2023

The human brain has hundreds of billions of neurons and at least 7 million dendrites have been hypothesized to exist for each neuron, with over 100 trillion neuron–neuron, neuron–muscle, and neuron–endocrine cell synapses [...]
DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes
Authors: Xavier Alexandre , Maltby Vicki E. , Ewing Ewoud , Campagna Maria Pia , Burnard Sean M. , Tegner Jesper N. , Slee Mark , Butzkueven Helmut , Kockum Ingrid , Kular Lara ,   Ausimmune/AusLong Investigators Group, Jokubaitis Vilija G. , Kilpatrick Trevor , Alfredsson Lars , Jagodic Maja , Ponsonby Anne-Louise , Taylor Bruce V. , Scott Rodney J. , Lea Rodney A. , Lechner-Scott Jeannette
Published: August 2023

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.
Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber’s Hereditary Optic Neuropathy (LHON) Subjects
Authors: Baglivo Mirko , Nasca Alessia , Lamantea Eleonora , Vinci Stefano , Spagnolo Manuela , Marchet Silvia , Prokisch Holger , Catania Alessia , Lamperti Costanza , Ghezzi Daniele
Published: August 2023

Leber’s hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.
ECO4RUPA: 5G-IoT Inclusive and Intelligent Routing Ecosystem with Low-Cost Air Quality Monitoring
Authors: Fayos-Jordan Rafael , Araiz-Chapa Raquel , Felici-Castell Santiago , Segura-Garcia Jaume , Perez-Solano Juan J. , Alcaraz-Calero Jose M.
Published: August 2023

The increase and diversity of low-cost air quality (AQ) sensors, as well as their flexibility and low power consumption, offers us the opportunity to integrate them into broad AQ wireless sensor networks, with the aim of enabling real-time monitoring and higher spatial sampling density of pollution in all parts of cities. Considering that the vast majority of the population lives in cities and the increase in respiratory/allergic problems in a large part of the population, it is of great interest to offer services and applications to improve their quality of life by avoiding pollution exposure in their movements in the open air. In the ECO4RUPA project, we focus on this kind of service, proposing an inclusive and intelligent routing ecosystem carried out using a network of low-cost AQ sensors with the support of 5G communications along with official AQ monitoring stations, using spatial interpolation techniques to enhance its spatial resolution. The goal of this service is to calculate healthy walking and/or cycling routes according to the particular citizen’s profile and needs. We provide and analyse the results of the proposed route planner under different scenarios (different timetables, congestion road traffic, and routes) and different user profiles, with a special interest in citizens with asthma and pregnant women, since both have special needs. In summary, our approach can lead to an approximately average reduction in pollution exposure of 17.82% while experiencing an approximately average increase in distance travelled of 9.8%.
First-Trimester Ultrasound Imaging for Prenatal Assessment of the Extended Cardiovascular System Using the Cardiovascular System Sonographic Evaluation Algorithm (CASSEAL)
Authors: Gambacorti-Passerini Zita M. , Martínez Payo Cristina , Arribas Coral Bravo , Larroca Santiago García-Tizón , García-Honduvilla Natalio , Ortega Miguel A. , Fernández-Pachecho Ricardo Pérez , De León Luis Juan
Published: August 2023

Introduction and objectives: To compare fetal images obtained at the first- and second-trimester ultrasound scan when applying the Cardiovascular System Sonographic Evaluation Algorithm (CASSEAL). Methods: Using the CASSEAL protocol, nine sequential axial views were acquired in B-mode and color Doppler at the first- and second-trimester ultrasound scans, visualizing the main components of the extended fetal cardiovascular system. Images were compared qualitatively between both trimesters. Results: We obtained comparable images for all the nine axial views described in the CASSEAL protocol, with few differences and limitations. Conclusions: The CASSEAL protocol is reproducible in the first trimester, and could help in the early detection of fetal cardiovascular abnormalities. It represents a promising additional tool in order to increase the CHD detection rate.
Between-Sex Differences in Risk Factors for Cardiovascular Disease among Patients with Myocardial Infarction—A Systematic Review
Authors: Barton Jack Charles , Wozniak Anna , Scott Chloe , Chatterjee Abhisekh , Titterton Greg Nathan , Corrigan Amber Elyse , Kuri Ashvin , Shah Viraj , Soh Ian , Kaski Juan Carlos
Published: August 2023

Between-sex differences in the presentation, risk factors, management, and outcomes of acute myocardial infarction (MI) are well documented. However, as such differences are highly sensitive to cultural and social changes, there is a need to continuously re-evaluate the evidence. The present contemporary systematic review assesses the baseline characteristics of men and women presenting to secondary, tertiary, and quaternary centres with acute myocardial infarction (MI). Over 1.4 million participants from 18 studies, including primary prospective, cross sectional and retrospective observational studies, as well as secondary analysis of registry data are included in the study. The study showed that women were more likely than men to have a previous diagnosis of diabetes, hypertension, cerebrovascular disease, and heart failure. They also had lower odds of presenting with previous ischaemic heart disease and angina, dyslipidaemia, or a smoking history. Further work is necessary to understand the reasons for these differences, and the role that gender-specific risk factors may have in this context. Moreover, how these between-gender differences are implicated in management and outcomes also requires further work.
Management of Spinal Metastasis by Minimally Invasive Surgical Techniques: Surgical Principles and Indications—A Literature Review
Authors: Meyer Mikael , Farah Kaissar , Aurélie Toquart , Graillon Thomas , Dufour Henry , Fuentes Stephane
Published: August 2023

Background: Spinal metastasis is becoming more frequent. This raises the topics of pain and neurological complications, which worsen the functional and survival prognosis of oncological population patients. Surgical treatment must be as complete as possible in order to decompress and stabilize without delaying the management of the oncological disease. Minimally invasive spine surgical techniques inflict less damage on the musculocutaneous plan than opened ones. Methods: Different minimally invasive techniques are proposed in this paper for the management of spinal metastasis. We used our experience, developed degenerative and traumatic pathologies, and referred to many authors, establishing a narrative review of our local practice. Results: Forty-eight articles were selected, and these allowed us to describe the different techniques: percutaneous methods such as vertebro/kyphoplasty, osteosynthesis, mini-open surgery, or that through a posterior or anterior approach. Also, some studies detail the contribution of new technologies, such as intraoperative CT scan and robotic assistance. Conclusions: It seems essential to offer a lasting solution to a spinal problem, such as in the form of pain relief, stabilization, and decompression. Our department has embraced a multidisciplinary and multidimensional approach to MISS, incorporating cutting-edge technologies and evidence-based practices.