bluuebunny/crossref_metadata_2025 huggingface dataset:
Moving Forward from Moral Injury: A Mixed Methods Study Investigating the Use of 3MDR for Treatment-Resistant PTSD
Authors: Smith-MacDonald Lorraine , Jones Chelsea , Brown Matthew R. G. , Dunleavy Rachel S. , VanderLaan Annelies , Kaneva Zornitsa , Hamilton Tristin , Burback Lisa , Vermetten Eric , Brémault-Phillips Suzette
Published: April 2023

Background: Exposure to trauma and potentially morally injurious events may lead to moral injury (MI). The link between MI and posttraumatic stress disorder (PTSD) may have particularly relevant implications for treatment-resistant PTSD (TR-PTSD). Multi-modal Motion-Assisted Memory Desensitization and Reconsolidation (3MDR), a technology-assisted exposure-based trauma therapy that has been used in the treatment of PTSD, may also be an acceptable modality for patients in the treatment of TR-PTSD and MI. This proof-of-concept study aimed to investigate (1) whether MI co-occurs in military members (MMs) and veterans with TR-PTSD, and (2) the perspectives of MMs and veterans with TR-PTSD utilizing 3MDR for MI. Methods: This study employed a mixed-methods clinical trial. Military Members and veterans participated in this study (N = 11) through self-reported questionnaires, video recordings of treatment sessions, and semi-structured interviews post-session and post-intervention, with longitudinal follow-up to 6 months. Results: MI scores correlated with self-reported measures of mental health symptoms related to PTSD. The thematic analysis revealed three emergent themes: (1) Realities of War, (2) Wrestling Scruples, and (3) Moral Sensemaking. Conclusion: MI was highly correlated with TR-PTSD and themes regarding MI. This result, while preliminary, allows for the postulation that MI may be contributing to the continuation of PTSD symptoms in TR-PTSD, and that 3MDR may be an acceptable modality for addressing these symptoms in MMs and veterans.
Relevance and Feasibility of Group Traumatic Episode Protocol Delivered to Migrants: A Pilot Field Study
Authors: Vignaud Philippe , Chauliac Nicolas , Contamin Emmanuel , Richer Sébastien , Vuillermoz Cécile , Brunelin Jérôme , Prieto Nathalie
Published: April 2023

Introduction: Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD) are commonly observed in migrants. Although Eye Movement Desensitization and Reprocessing (EMDR) can be helpful to treat these diseases, it remains difficult to propose EMDR as an individual intervention in help-seeking migrants. Group EMDR, like Group Traumatic Episode Protocol (G-TEP), which was built around the 8 phases of the original EMDR protocol, could offer an effective treatment to a large number of people. It may also be more resource-efficient to provide psychiatric care to migrants. Methods: In this open-label trial, the feasibility and the effectiveness of a 6-session G-TEP intervention was investigated in a group of 10 migrants. Results: The intervention was well tolerated by participants. The final attrition rate was 10%. After the intervention, there was a 28.2% significant decrease in PTSD and complex PTSD symptoms, as measured by the International Trauma Questionnaires (total_ITQ) scores (p = 0.013) and a trend towards a significant decrease in MDD symptoms, as measured with the Patient Health Questionnaire (PHQ-9) (p = 0.057). Conclusions: G-TEP may be effective in decreasing PTSD symptoms in migrants. The accessibility, low-cost, and very structured features of G-TEP may make its implementation sustainable in the field of psychiatric care for migrants.
Patients’ Perceptions of Exercise-Based Cardiac Telerehabilitation after a Myocardial Infarction—A Qualitative Study
Authors: Nilsson Ulrika , Öberg Birgitta , Bäck Maria
Published: April 2023

To be able to design telerehabilitation programs targeting the needs and preferences of end-users, patients’ in-depth perspectives are needed. To date, such studies are lacking and, therefore, the aim of the present study was to describe patients’ perceptions of performing exercise-based cardiac telerehabilitation after a myocardial infarction (MI). Individual semi-structured interviews were performed with 15 patients (3 women, median age 69 years) after an MI who had participated in exercise-based cardiac telerehabilitation for three months. The interviews were transcribed verbatim and analyzed with inductive content analysis. An overall theme was defined as “Cardiac telerehabilitation—a new alternative for exercising that is easily accessible and up to date”. Four categories, including “The important role of a physical therapist with expert knowledge”, “Prerequisites playing an important role in the willingness to participate”, “Making exercise accessible and adjustable” and “Inspiring future exercise”, and 15 subcategories were identified. Understanding the patient’s perspective is an important key to further improving and successfully implementing exercise-based cardiac telerehabilitation, as an alternative or adjunct to traditional, centre-based programs. The findings can serve to improve patient–physiotherapist interactions and to inform important aspects related to exercise, technology and a sense of security from an exercise-based cardiac telerehabilitation program.
Expectations Regarding Gastein Healing Gallery Treatment and Their Connection to Health-Related Quality of Life
Authors: Toussaint Loren , Huynh Kien , Kohls Niko , Sirois Fuschia , Alberts Hannah , Hirsch Jameson , Hanshans Christian , Nguyen Quang Anh , van der Zee-Neuen Antje , Offenbaecher Martin
Published: April 2023

The present study examines connections between patient expectations and health-related quality of life. We explore a key distinction between expectations about general health and expectations for functional improvement. Patients were 1444 individuals with multiple conditions experiencing chronic pain who were seeking treatment at the Gastein Healing Gallery in Böckstein, near Bad Gastein, Austria. In addition to measures of expectations, patients completed measures of pain, mental and physical health, life satisfaction, fatigue, and sleep problems. Structural equation models were used to fit a latent variable model where both expectation variables were used to predict health-related quality of life. Results showed that expectations regarding potential functional improvement resulting from treatments at the Gastein Healing Gallery were associated with improved health-related quality of life. Expectations about general health improvements related to treatment were not associated with health-related quality of life. To facilitate optimal healing, clinicians may decide to emphasize expectations about functional recovery when discussing treatment methods similar to those offered at the Gastein Healing Gallery, and in so doing, health-related quality of life may benefit.
Impact of Environmental Exposure on Chronic Diseases in China and Assessment of Population Health Vulnerability
Authors: Huang Zhibin , Cao Chunxiang , Xu Min , Yang Xinwei
Published: April 2023

Although numerous epidemiological studies have demonstrated a relationship between environmental factors and chronic diseases, there is a lack of comprehensive population health vulnerability assessment studies from the perspective of environmental exposure, population sensitivity and adaptation on a regional scale. To address this gap, this study focused on six high-mortality chronic diseases in China and constructed an exposure–sensitivity–adaptability framework-based index system using multivariate data. The constructed system effectively estimated health vulnerability for the chronic diseases. The R-square between vulnerability and mortality rates for respiratory diseases and malignant tumors exceeded 0.7 and was around 0.6 for the other four chronic diseases. In 2020, Chongqing exhibited the highest vulnerability to respiratory diseases. For heart diseases, vulnerability values exceeding 0.5 were observed mainly in northern and northeastern provinces. Vulnerability values above 0.5 were observed in Jiangsu, Shanghai, Tianjin, Shandong and Liaoning for cerebrovascular diseases and malignant tumors. Shanghai had the highest vulnerability to endogenous metabolic diseases, and Tibet exhibited the highest vulnerability to digestive system diseases. The main related factor analysis results show that high temperature and humidity, severe temperature fluctuations, serious air pollution, high proportion of middle-aged and elderly population, as well as high consumption of aquatic products, red meat and eggs increased health vulnerability, while increasing per capita educational resources helped reduce vulnerability.
Crystal Chemistry of the Copper Oxalate Biomineral Moolooite: The First Single-Crystal X-ray Diffraction Studies and Thermal Behavior
Authors: Kornyakov Ilya V. , Gurzhiy Vladislav V. , Kuz’mina Mariya A. , Krzhizhanovskaya Maria G. , Chukanov Nikita V. , Chislov Mikhail V. , Korneev Anatolii V. , Izatulina Alina R.
Published: April 2023

Moolooite, Cu(C2O4)·nH2O, is a typical biomineral which forms due to Cu-bearing minerals coming into contact with oxalic acid sources such as bird guano deposits or lichens, and no single crystals of moolooite of either natural or synthetic origin have been found yet. This paper reports, for the first time, on the preparation of single crystals of a synthetic analog of the copper-oxalate biomineral moolooite, and on the refinement of its crystal structure from the single-crystal X-ray diffraction (SCXRD) data. Along with the structural model, the SCXRD experiment showed the significant contribution of diffuse scattering to the overall diffraction data, which comes from the nanostructural disorder caused by stacking faults of Cu oxalate chains as they lengthen. This type of disorder should result in the chains breaking, at which point the H2O molecules may be arranged. The amount of water in the studied samples did not exceed 0.15 H2O molecules per formula unit. Apparently, the mechanism of incorporation of H2O molecules governs the absence of good-quality single crystals in nature and a lack of them in synthetic experiments: the more H2O content in the structure, the stronger the disorder will be. A description of the crystal structure indicates that the ideal structure of the Cu oxalate biomineral moolooite should not contain H2O molecules and should be described by the Cu(C2O4) formula. However, it was shown that natural and synthetic moolooite crystals contain a significant portion of “structural” water, which cannot be ignored. Considering the substantially variable amount of water, which can be incorporated into the crystal structure, the formula Cu(C2O4)·nH2O for moolooite is justified.
Intelligent De Novo Design of Novel Antimicrobial Peptides against Antibiotic-Resistant Bacteria Strains
Authors: Lin Tzu-Tang , Yang Li-Yen , Lin Chung-Yen , Wang Ching-Tien , Lai Chia-Wen , Ko Chi-Fong , Shih Yang-Hsin , Chen Shu-Hwa
Published: April 2023

Because of the growing number of clinical antibiotic resistance cases in recent years, novel antimicrobial peptides (AMPs) may be ideal for next-generation antibiotics. This study trained a Wasserstein generative adversarial network with gradient penalty (WGAN-GP) based on known AMPs to generate novel AMP candidates. The quality of the GAN-designed peptides was evaluated in silico, and eight of them, named GAN-pep 1–8, were selected by an AMP Artificial Intelligence (AI) classifier and synthesized for further experiments. Disc diffusion testing and minimum inhibitory concentration (MIC) determinations were used to identify the antibacterial effects of the synthesized GAN-designed peptides. Seven of the eight synthesized GAN-designed peptides displayed antibacterial activity. Additionally, GAN-pep 3 and GAN-pep 8 presented a broad spectrum of antibacterial effects and were effective against antibiotic-resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus and carbapenem-resistant Pseudomonas aeruginosa. GAN-pep 3, the most promising GAN-designed peptide candidate, had low MICs against all the tested bacteria. In brief, our approach shows an efficient way to discover AMPs effective against general and antibiotic-resistant bacteria strains. In addition, such a strategy also allows other novel functional peptides to be quickly designed, identified, and synthesized for validation on the wet bench.
Peach DELLA Protein PpeDGYLA Is Not Degraded in the Presence of Active GA and Causes Dwarfism When Overexpressed in Poplar and Arabidopsis
Authors: Chen Yun , Zhang Mengmeng , Wang Xiaofei , Shao Yun , Hu Xinyue , Cheng Jun , Zheng Xianbo , Tan Bin , Ye Xia , Wang Wei , Li Jidong , Li Ming , Zhang Langlang , Feng Jiancan
Published: April 2023

Controlling the tree size of fruit species such as peach can reduce the amount of labor and input needed for orchard management. The phytohormone gibberellin (GA) positively regulates tree size by inducing degradation of the GA signaling repressor DELLA. The N-terminal DELLA domain in this protein is critical for its GA-dependent interaction with the GA receptor GID1 and the resulting degradation of the DELLA protein, which allows for growth-promoting GA signaling. In this study, a DELLA family member, PpeDGYLA, contains a DELLA domain but has amino acid changes in three conserved motifs (DELLA into DGYLA, LEQLE into LERLE, and TVHYNP into AVLYNP). In the absence or presence of GA3, the PpeDGYLA protein did not interact with PpeGID1c and was stable in 35S-PpeDGYLA peach transgenic callus. The overexpression of PpeDGYLA in both polar and Arabidopsis showed an extremely dwarfed phenotype, and these transgenic plants were insensitive to GA3 treatment. PpeDGYLA could interact with PpeARF6-1 and -2, supposed growth-promoting factors. It is suggested that the changes in the DELLA domain of PpeDGYLA may, to some extent, account for the severe dwarf phenotype of poplar and Arabidopsis transgenic plants. In addition, our study showed that the DELLA family contained three clades (DELLA-like, DELLA, and DGLLA). PpeDGYLA clustered into the DGLLA clade and was expressed in all of the analyzed tissues. These results lay the foundation for the further study of the repression of tree size by PpeDGYLA.
Multi-Targeting Anticancer Activity of a New 4-Thiazolidinone Derivative with Anti-HER2 Antibodies in Human AGS Gastric Cancer Cells
Authors: Gornowicz Agnieszka , Lesyk Roman , Czarnomysy Robert , Holota Serhii , Shepeta Yulia , Popławska Bożena , Podolak Magdalena , Szymanowski Wojciech , Bielawski Krzysztof , Bielawska Anna
Published: April 2023

Combining chemotherapy with immunotherapy still remains a regimen in anticancer therapy. Novel 4-thiazolidinone-bearing hybrid molecules possess well-documented anticancer activity, and together with anti-HER2 antibodies, may represent a promising strategy in treating patients with gastric cancer with confirmed human epidermal growth factor receptor 2 (HER2) expression. The aim of the study was to synthesize a new 4-thiazolidinone derivative (Les-4367) and investigate its molecular mechanism of action in combination with trastuzumab or pertuzumab in human AGS gastric cancer cells. AGS cell viability and antiproliferative potential were examined. The effect of the tested combinations as well as monotherapy on apoptosis and autophagy was also determined. Metalloproteinase-2 (MMP-2), intercellular adhesion molecule 1 (ICAM-1), pro-inflammatory and anti-inflammatory cytokine concentrations were also demonstrated by the ELISA technique. We proved that pertuzumab and trastuzumab were very effective in increasing the sensitivity of AGS gastric cancer cells to novel Les-4367. The molecular mechanism of action of the tested combination is connected with the induction of apoptosis. Additionally, the anticancer activity is not associated with the autophagy process. Decreased concentrations of pro-inflammatory cytokines, MMP-2 and ICAM-1—were observed. The novel combination of drugs based on anti-HER2 antibodies with Les-4367 is a promising strategy against AGS gastric cancer cells.
The Effect of Dietary Factors on Cancer
Authors: Benvenuto Monica , Bei Roberto
Published: April 2023

The effects of dietary factors on cancer have been widely studied for several decades [...]
Bilateral Shifts in Deuterium Supply Similarly Change Physiology of the Pituitary–Thyroid Axis, but Differentially Influence Na+/I− Symporter Production
Authors: Yaglova Nataliya V. , Obernikhin Sergey S. , Timokhina Ekaterina P. , Yaglov Valentin V. , Tsomartova Dibakhan A. , Nazimova Svetlana V. , Tsomartova Elina S. , Ivanova Marina Y. , Chereshneva Elizaveta V. , Lomanovskaya Tatiana A.
Published: April 2023

Deuterium, a stable isotope of hydrogen, is abundant in organisms. It is known to produce various biological effects. However, its impact in thyroid hormone synthesis and secretion is poorly studied. The aim of this investigation was to evaluate the dynamics of thyroid hormones and pituitary thyroid-stimulating hormone secretion during bilateral shifts in deuterium supply and assess a possible role of the Na+/I− symporter (NIS), the main iodide transporter, in altered thyroid function. The experiment was performed on adult male Wistar rats, which consumed deuterium-depleted ([D] = 10 ppm) and deuterium-enriched ([D] = 500,000 ppm) water for 21 days. The assessment of total thyroxine and triiodothyronine and their free fractions, as well as thyroid-stimulating hormone in blood serum, revealed the rapid response of the thyroid gland to shifts in the deuterium/protium balance. The present investigation shows that the bilateral changes in the deuterium body content similarly modulate thyroid hormone production and functional activity of the pituitary gland, but the responses of the thyroid and pituitary glands differ. The response of the thyroid cells was to increase the synthesis of the hormones and the pituitary thyrotropes, in order to reduce the production of the thyroid-stimulating hormone. The evaluation of NIS serum levels found a gradual increase in the rats that consumed deuterium-enriched water and no differences in the group exposed to deuterium depletion. NIS levels in both groups did not correlate with thyroid hormones and pituitary thyroid-stimulating hormone production. The data obtained show that thyroid gland has a higher sensitivity to shifts in the deuterium body content than the hypothalamic–pituitary complex, which responded later but similarly in the case of deuteration or deuterium depletion. It indicates a different sensitivity of the endocrine glands to alterations in deuterium content. It suggests that thyroid hormone production rate may depend on deuterium blood/tissue and cytosol/organelle gradients, which possibly disturb the secretory process independently of the NIS.
Moisturizing and Antioxidant Effects of Artemisia argyi Essence Liquid in HaCaT Keratinocytes
Authors: Wang Ziwen , Wang Qiaoli , Zhong Wenshen , Liang Feng , Guo Yuying , Wang Yifei , Wang Zhiping
Published: April 2023

Artemisia argyi essence liquid (AL) is an aqueous solution extracted from A. argyi using CO2 supercritical fluid extraction. There have been few investigations on the aqueous solution of A. argyi extracted via CO2 supercritical fluid extraction. This study aimed to explore the moisturizing and antioxidant effects of AL and to clarify the potential mechanism underlying those effects. Expression levels of skin moisture-related components and the H2O2-induced oxidative stress responses in human keratinocyte cells were measured via quantitative RT-qPCR, Western blot, and immunofluorescence. Our results showed that AL enhanced the expression of AQP3 and HAS2 by activating the EGFR-mediated STAT3 and MAPK signaling pathways. In addition, AL can play an antioxidant role by inhibiting the NF-κB signaling pathway and activating the Nrf2/HO-1 signaling pathway, consequently increasing the expression of antioxidant enzymes (GPX1, SOD2) and decreasing the production of reactive oxygen species (ROS). This study revealed that AL could be used as a potential moisturizing and antioxidant cosmetic ingredient.
Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling
Authors: Long Huideng , Hou Yue , Li Jun , Song Chunhua , Ge Zheng
Published: April 2023

Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.
Transcriptomic Differences Underlying the Activin-A Induced Large Osteoclast Formation in Both Healthy Control and Fibrodysplasia Ossificans Progressiva Osteoclasts
Authors: Schoenmaker Ton , Zwaak Joy , Loos Bruno G. , Volckmann Richard , Koster Jan , Eekhoff E. Marelise W. , de Vries Teun J.
Published: April 2023

Fibrodysplasia Ossificans Progressiva (FOP) is a very rare genetic disease characterized by progressive heterotopic ossification (HO) of soft tissues, leading to immobility and premature death. FOP is caused by a mutation in the Activin receptor Type 1 (ACVR1) gene, resulting in altered responsiveness to Activin-A. We recently revealed that Activin-A induces fewer, but larger and more active, osteoclasts regardless of the presence of the mutated ACVR1 receptor. The underlying mechanism of Activin-A-induced changes in osteoclastogenesis at the gene expression level remains unknown. Transcriptomic changes induced by Activin-A during osteoclast formation from healthy controls and patient-derived CD14-positive monocytes were studied using RNA sequencing. CD14-positive monocytes from six FOP patients and six age- and sex-matched healthy controls were differentiated into osteoclasts in the absence or presence of Activin-A. RNA samples were isolated after 14 days of culturing and analyzed by RNA sequencing. Non-supervised principal component analysis (PCA) showed that samples from the same culture conditions (e.g., without or with Activin-A) tended to cluster, indicating that the variability induced by Activin-A treatment was larger than the variability between the control and FOP samples. RNA sequencing analysis revealed 1480 differentially expressed genes induced by Activin-A in healthy control and FOP osteoclasts with p(adj) < 0.01 and a Log2 fold change of ≥±2. Pathway and gene ontology enrichment analysis revealed several significantly enriched pathways for genes upregulated by Activin-A that could be linked to the differentiation or function of osteoclasts, cell fusion or inflammation. Our data showed that Activin-A has a substantial effect on gene expression during osteoclast formation and that this effect occurred regardless of the presence of the mutated ACVR1 receptor causing FOP.
Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma
Authors: Peng Chen-Ching , Sirivolu Shreya , Pike Sarah , Kim Mary E. , Reiser Bibiana , Li Hong-Tao , Liang Gangning , Xu Liya , Berry Jesse L.
Published: April 2023

Gene expression profiling (GEP) is clinically validated to stratify the risk of metastasis by assigning uveal melanoma (UM) patients to two highly prognostic molecular classes: class 1 (low metastatic risk) and class 2 (high metastatic risk). However, GEP requires intraocular tumor biopsy, which is limited by small tumor size and tumor heterogeneity; furthermore, there are small risks of retinal hemorrhage, bleeding, or tumor dissemination. Thus, ocular liquid biopsy has emerged as a less-invasive alternative. In this study, we seek to determine the aqueous humor (AH) proteome related to the advanced GEP class 2 using diagnostic AH liquid biopsy specimens. Twenty AH samples were collected from patients with UM, grouped by GEP classes. Protein expression levels of 1472 targets were analyzed, compared between GEP classes, and correlated with clinical features. Significant differentially expressed proteins (DEPs) were subjected to analysis for cellular pathway and upstream regulator identification. The results showed that 45 DEPs detected in the AH could differentiate GEP class 1 and 2 at diagnosis. IL1R and SPRY2 are potential upstream regulators for the 8/45 DEPs that contribute to metastasis-related pathways. AH liquid biopsy offers a new opportunity to determine metastatic potential for patients in the absence of tumor biopsy.
The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice
Authors: Zahid Saadia , Dafre Alcir L. , Currais Antonio , Yu Jingting , Schubert David , Maher Pamela
Published: April 2023

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer’s disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.
Molecular Dynamics Simulations Reveal the Conformational Transition of GH33 Sialidases
Authors: Cao Xueting , Yang Xiao , Xiao Min , Jiang Xukai
Published: April 2023

Sialidases are increasingly used in the production of sialyloligosaccharides, a significant component of human milk oligosaccharides. Elucidating the catalytic mechanism of sialidases is critical for the rational design of better biocatalysts, thereby facilitating the industrial production of sialyloligosaccharides. Through comparative all-atom molecular dynamics simulations, we investigated the structural dynamics of sialidases in Glycoside Hydrolase family 33 (GH33). Interestingly, several sialidases displayed significant conformational transition and formed a new cleft in the simulations. The new cleft was adjacent to the innate active site of the enzyme, which serves to accommodate the glycosyl acceptor. Furthermore, the residues involved in the specific interactions with the substrate were evolutionarily conserved in the whole GH33 family, highlighting their key roles in the catalysis of GH33 sialidases. Our results enriched the catalytic mechanism of GH33 sialidases, with potential implications in the rational design of sialidases.
The Study of the Association of Polymorphisms in LSP1, GPNMB, PDPN, TAGLN, TSPO, and TUBB6 Genes with the Risk and Outcome of Ischemic Stroke in the Russian Population
Authors: Khrunin Andrey V. , Khvorykh Gennady V. , Arapova Anna S. , Kulinskaya Anna E. , Koltsova Evgeniya A. , Petrova Elizaveta A. , Kimelfeld Ekaterina I. , Limborska Svetlana A.
Published: April 2023

To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an analysis of the results obtained from animal models of brain ischemia could be helpful. To this end, we developed a bioinformatic approach for exploring single-nucleotide polymorphisms (SNPs) in human orthologs of rat genes expressed differentially after induced brain ischemia. Using this approach, we identified and analyzed 11 SNPs from 6 genes in 553 Russian individuals (331 patients with IS and 222 controls). We assessed the association of SNPs with the risk of IS and IS outcomes. We found that the SNPs rs858239 (GPNMB), rs907611 (LSP1), and rs494356 (TAGLN) were associated with different parameters of IS functional outcomes. In addition, the SNP rs1261025 (PDPN) was associated significantly with IS itself (p = 0.0188, recessive model). All these associations were demonstrated for the first time. Analysis of the literature suggests that they should be characterized as being inflammation related. This supports the pivotal role of inflammation in both the incidence of stroke and post-stroke outcomes. We believe the findings reported here will help with stroke prognosis in the future.
Analyses of the Cellular Interactions between the Ossification of Collagen-Based Barrier Membranes and the Underlying Bone Defects
Authors: Alkildani Said , Ren Yanru , Liu Luo , Rimashevskiy Denis , Schnettler Reinhard , Radenković Milena , Najman Stevo , Stojanović Sanja , Jung Ole , Barbeck Mike
Published: April 2023

Barrier membranes are an essential tool in guided bone Regeneration (GBR), which have been widely presumed to have a bioactive effect that is beyond their occluding and space maintenance functionalities. A standardized calvaria implantation model was applied for 2, 8, and 16 weeks on Wistar rats to test the interactions between the barrier membrane and the underlying bone defects which were filled with bovine bone substitute materials (BSM). In an effort to understand the barrier membrane’s bioactivity, deeper histochemical analyses, as well as the immunohistochemical detection of macrophage subtypes (M1/M2) and vascular endothelial cells, were conducted and combined with histomorphometric and statistical approaches. The native collagen-based membrane was found to have ossified due to its potentially osteoconductive and osteogenic properties, forming a “bony shield” overlying the bone defects. Histomorphometrical evaluation revealed the resorption of the membranes and their substitution with bone matrix. The numbers of both M1- and M2-macrophages were significantly higher within the membrane compartments compared to the underlying bone defects. Thereby, M2-macrophages significantly dominated the tissue reaction within the membrane compartments. Statistically, a correlation between M2-macropahges and bone regeneration was only found at 2 weeks post implantationem, while the pro-inflammatory limb of the immune response correlated with the two processes at 8 weeks. Altogether, this study elaborates on the increasingly described correlations between barrier membranes and the underlying bone regeneration, which sheds a light on the understanding of the immunomodulatory features of biomaterials.
Characterizing the Interplay of Lymphocytes in Graves’ Disease
Authors: Hansen Mackenzie , Cheever Abigail , Weber K. , O’Neill Kim
Published: April 2023

Graves’ disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves’ disease can lead to improved treatment strategies and novel drug targets.
Antibody Profile, Gene Expression and Serum Cytokines in At-Risk Infants before the Onset of Celiac Disease
Authors: Auricchio Renata , Galatola Martina , Cielo Donatella , Rotondo Roberta , Carbone Fortunata , Mandile Roberta , Carpinelli Martina , Vitale Serena , Matarese Giuseppe , Gianfrani Carmen , Troncone Riccardo , Auricchio Salvatore , Greco Luigi
Published: April 2023

Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from the Italian cohorts of the PREVENT-CD and Neocel projects, as well as the relationship between antibody production and systemic inflammation. HLA DQ2 and/or DQ8 infants from families with a CeD case were followed from birth. Out of 220 at-risk children, 182 had not developed CeD by 6 years of age (CTRLs), and 38 developed celiac disease (CeD). The profiles of serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10, IL12p70, IL17A and TNFα) and the expression of selected genes (FoxP3, IL10, TGFβ, INFγ, IL4 and IL2) were evaluated in 46 children (20 CeD and 26 CTRLs). Among the 182 healthy CTRLs, 28 (15.3%) produced high levels of AGA-IgA (AGA+CTRLs), and none developed anti-tTG-IgA or DGP-IgA, compared to 2/38 (5.3%) CeD infants (Chi Sq. 5.97, p = 0.0014). AGAs appeared earlier in CTRLs than in those who developed CeD (19 vs. 28 months). Additionally, the production of AGAs in CeD overlapped with the production of DGP and anti-tTG. In addition, gene expression as well as serum cytokine levels discriminated children who developed CeD from CTRLs. In conclusion, these findings suggest that the early and isolated production of AGA-IgA antibodies is a CeD-tolerogenic marker and that changes in gene expression and cytokine patterns precede the appearance of anti-tTG antibodies.
Bones and Hormones: Interaction between Hormones of the Hypothalamus, Pituitary, Adipose Tissue and Bone
Authors: Niwczyk Olga , Grymowicz Monika , Szczęsnowicz Aleksandra , Hajbos Marta , Kostrzak Anna , Budzik Michał , Maciejewska-Jeske Marzena , Bala Gregory , Smolarczyk Roman , Męczekalski Błażej
Published: April 2023

The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances in research over the last decade have shone light on the various hormones that influence this process, modulating the metabolism and structural integrity of bone. More recently, novel and non-traditional functions of hypothalamic, pituitary, and adipose hormones and their effects on bone homeostasis have been proposed. This review highlights recent work on physiological bone remodeling and discusses our knowledge, as it currently stands, on the systemic interplay of factors regulating this interaction. In this review, we provide a summary of the literature on the relationship between bone physiology and hormones including kisspeptin, neuropeptide Y, follicle-stimulating hormone (FSH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), leptin, and adiponectin. The discovery and understanding of this new functionality unveils an entirely new layer of physiologic circuitry.
Imaging Flow Cytometry Demonstrates Physiological and Morphological Diversity within Treated Probiotic Bacteria Groups
Authors: Kiepś Jakub , Juzwa Wojciech , Dembczyński Radosław
Published: April 2023

Probiotic bacteria can be introduced to stresses during the culturing phase as an alternative to the use of protectants and coating substances during drying. Accurate enumeration of the bacterial count in a probiotic formulation can be provided using imaging flow cytometry (IFC). IFC overcomes the weak points of conventional, commonly used flow cytometry by combining its statistical power with the imaging content of microscopy in one system. Traditional flow cytometers only collect the fluorescence signal intensities, while IFC provides many more steps as it correlates the data on the measured parameters of fluorescence light with digitally processed images of the analyzed cells. As an alternative to standard methods (plate cell counts and traditional flow cytometry) IFC provides additional insight into the physiology and morphology of the cell. The use of complementary dyes (RedoxSensorTM Green and propidium iodide) allows for the designation of groups based on their metabolic activity and membrane damage. Additionally, cell sorting is incorporated to assess each group in terms of growth on different media (MRS-Agar and MRS broth). Results show that the groups with intermediate metabolic activity and some degree of cellular damage correspond with the description of viable but nonculturable cells.
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling
Authors: Jhuo Shih-Jie , Lin Yi-Hsiung , Liu I-Hsin , Lin Tsung-Hsien , Wu Bin-Nan , Lee Kun-Tai , Lai Wen-Ter
Published: April 2023

Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca2+ distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca2+ overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca2+ overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.
Salvianolic-Acid-B-Loaded HA Self-Healing Hydrogel Promotes Diabetic Wound Healing through Promotion of Anti-Inflammation and Angiogenesis
Authors: Zhou Guoying , Zhu Jiayan , Jin Liang , Chen Jing , Xu Ruojiao , Zhao Yali , Yan Tingzi , Wan Haitong
Published: April 2023

Inflammatory dysfunction and angiogenesis inhibition are two main factors leading to the delayed healing of diabetic wounds. Hydrogels with anti-inflammatory and angiogenesis-promoting effects have been considered as promising wound care materials. Herein, a salvianolic acid B (SAB)-loaded hyaluronic acid (HA) self-healing hydrogel (HA/SAB) with anti-inflammatory and pro-angiogenesis capacities for diabetic wound healing is reported. The HA hydrogel was prepared via the covalent cross-linking of aldehyde groups in oxidized HA (OHA) and hydrazide groups in adipic dihydrazide (ADH)-modified HA (HA-ADH) with the formation of reversible acylhydrazone bonds. The obtained HA hydrogel exhibited multiple favorable properties such as porous structures, excellent self-healing properties, a sustainable release capacity of SAB, as well as excellent cytocompatibility. In addition, the effects of the SAB-loaded HA self-healing hydrogel were investigated via a full-thickness skin defect model using diabetic rats. The HA/SAB hydrogel showed enhanced skin regeneration effects with accelerated wound closure, shorter remaining dermal space length, thicker granulation tissue formation, and more collagen deposition. Furthermore, reduced inflammatory response and enhanced vascularization were found with HA/SAB2.5 hydrogel-treated wounds, indicating that the hydrogel promotes diabetic wound healing through the promotion of anti-inflammation and angiogenesis. Our results suggest that the fabricated SAB-loaded HA self-healing hydrogel is promising as a wound dressing for the treatment of diabetic wounds.
Identification of Orbivirus Non-Structural Protein 5 (NS5), Its Role and Interaction with RNA/DNA in Infected Cells
Authors: Mohd Jaafar Fauziah , Monsion Baptiste , Mertens Peter P. C. , Attoui Houssam
Published: April 2023

Bioinformatic analyses have predicted that orbiviruses encode an additional, small non-structural protein (NS5) from a secondary open reading frame on genome segment 10. However, this protein has not previously been detected in infected mammalian or insect cells. NS5-specific antibodies were generated in mice and were used to identify NS5 synthesised in orbivirus-infected BSR cells or cells transfected with NS5 expression plasmids. Confocal microscopy shows that although NS5 accumulates in the nucleus, particularly in the nucleolus, which becomes disrupted, it also appears in the cell cytoplasm, co-localising with mitochondria. NS5 helps to prevent the degradation of ribosomal RNAs during infection and reduces host-cell protein synthesis However, it helps to extend cell viability by supporting viral protein synthesis and virus replication. Pulldown studies showed that NS5 binds to ssRNAs and supercoiled DNAs and demonstrates interactions with ZBP1, suggesting that it modulates host-cell responses.
Genetic Variation among Heterodera schachtii Populations Coincided with Differences in Invasion and Propagation in Roots of a Set of Cruciferous Plants
Authors: Nuaima Rasha Haj , Heuer Holger
Published: April 2023

Genes of host plants and parasitic nematodes govern the plant–nematode interaction. The biological receptors and parasitism effectors are variable among plant species and nematode populations, respectively. In the present study, hatch testing and bioassays on cabbage, oilseed radish, and mustard were conducted to compare the biological characteristics among six populations of the beet cyst nematode Heterodera schachtii. Genetic patterns of the vap1 gene for the studied populations were distinct as shown by denaturing the gradient gel electrophoresis of PCR-amplified gene fragments. Concurrently, significant differences in the hatching rates, number of penetrated J2 in roots, and eggs/cyst ratios among the six nematode populations for the three cruciferous species were observed. In conclusion, analyzing the population genetic structure of H. schachtii plays a pivotal role in illustrating the variability in the plant–nematode interaction among its populations and plant species, which in its role leads to developing nematode management depending on plant resistance.
Neuroendocrine Neoplasms of the Gastrointestinal Tract versus Neuroendocrine Neoplasms of the Gynaecological Tract—Comparison of the Risk Factors and Non-Surgical Treatment Efficacy
Authors: Lorenz Anna , Lenkiewicz Sebastian , Kozłowski Mateusz , Kwiatkowski Sebastian , Cymbaluk-Płoska Aneta
Published: April 2023

Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a poor prognosis, especially when detected at an advanced stage. The basis of the treatment is resection, and non-surgical treatments are also standard in the treatment process. The situation is similar in even rarer neuroendocrine tumours of the reproductive tract, which are associated with an equally poor prognosis. In this article, we focus on learning about the risk factors (including genetic mutations) that increase the risk of the disease and comparing the effectiveness of non-surgical treatments—chemotherapy, radiotherapy, peptide receptor radionuclide therapy, somatostatin analogues, and immunotherapy. The efficacy of these treatments varies, and immunotherapy appears to be a promising form of treatment; however, this requires further research.
Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase
Authors: Kuo Ko-Lin , Chiang Chin-Wei , Chen Yi-Ming Arthur , Yu Chih-Chin , Lee Tzong-Shyuan
Published: April 2023

Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and GNMT knockout (GNMT−/−) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, GNMT−/− mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in GNMT−/− mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target.