bluuebunny/crossref_metadata_2025 huggingface dataset:
CSMD1 Mutations Are Associated with Increased Mutational Burden, Favorable Prognosis, and Anti-Tumor Immunity in Gastric Cancer
Authors: Huang Taobi , Liang Yuan , Zhang Huiyun , Chen Xia , Wei Hui , Sun Weiming , Wang Yuping
Published: October 2021

Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). To find specific gene mutations related to TMB and the prognosis of patients, the frequently mutated genes in gastric cancer patients from TCGA and ICGC were obtained and the correlation between gene mutation, TMB, and prognosis was analyzed. Furthermore, to clarify whether specific gene mutations can be used as predictive biomarkers of ICIs, a gene set enrichment analysis (GSEA) for immune pathways and an immune infiltration analysis were conducted. The results showed that CUB and Sushi multiple domains 1 (CSMD1) mutation (CSMD1-mut) were associated with higher TMB and better prognosis in patients. The genetic map showed that, compared with wild-type samples, the loss of chromosomes 4q, 5q, 8p, and 9p decreased and the status of microsatellite instability increased in the CSMD1-mut samples. The GSEA analysis showed that immune-related pathways were enriched in the CSMD1-mut samples. The immune infiltration analysis showed that the anti-tumor immune cells were upregulated and that the tumor-promoting immune cells were downregulated in the CSMD1-mut samples. The gene co-expression analysis showed that PD-L1 expression was higher in the CSMD1-mut samples. In summary, CSMD1-mut in gastric cancer was associated with increased TMB and favorable survival and may have potential significance in predicting the efficacy of anti-PD-L1.
Analysis of SI-Related BoGAPDH Family Genes and Response of BoGAPC to SI Signal in Brassica oleracea L.
Authors: Xie Qinqin , Zhang Hecui , Hu Dengke , Liu Qianying , Zuo Tonghong , Zhang Yizhong , Liu Yimei , Zhou Siru , Zhu Liquan
Published: October 2021

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is not only involved in carbohydrate metabolism, but also plays an important role in stress resistance. However, it has not been reported in Brassica oleracea. In this study, we performed a genome-wide identification of BoGAPDH in B. oleracea and performed cloning and expression analysis of one of the differentially expressed genes, BoGAPC. A total of 16 members of the BoGAPDH family were identified in B. oleracea, which were conserved, distributed unevenly on chromosomes and had tandem repeat genes. Most of the genes were down-regulated during self-pollination, and the highest expression was found in stigmas and sepals. Different transcriptome data showed that BoGAPDH genes were differentially expressed under stress, which was consistent with the results of qRT-PCR. We cloned and analyzed the differentially expressed gene BoGAPC and found that it was in the down-regulated mode 1 h after self-pollination, and the expression was the highest in the stigma, which was consistent with the result of GUS staining. The promoter region of the gene not only has stress response elements and plant hormone response elements, but also has a variety of specific elements for regulating floral organ development. Subcellular localization indicates that the BoGAPC protein is located in the cytoplasm and belongs to the active protein in the cytoplasm. The results of prokaryotic expression showed that the size of the BoGAPC protein was about 37 kDa, which was consistent with the expected results, indicating that the protein was induced in prokaryotic cells. The results of yeast two-hybrid and GST pull-down showed that the SRK kinase domain interacted with the BoGAPC protein. The above results suggest that the BoGAPDH family of B. oleracea plays an important role in the process of plant stress resistance, and the BoGAPC gene may be involved in the process of self-incompatibility in B. oleracea, which may respond to SI by encoding proteins directly interacting with SRK.
Potentially Mobilizable Geogenic As and Sb in an Agricultural Wetland Soil
Authors: Rouwane Asmaa , Grybos Malgorzata , Rabiet Marion , Guibaud Gilles
Published: October 2021

The mobility of arsenic (As) and antimony (Sb) in soils is controlled by several processes (adsorption/desorption, (co)precipitation/dissolution and oxidation/reduction), depending on various environmental factors that are often convoluted and site-dependent. This study investigated: (i) the content and solid-phase distribution of geogenic As and Sb in a vertical soil profile (0–130 cm) of an agricultural wetland subject into alternating oxic and anoxic conditions induced by periodic waterlogging and (ii) identifies the stability of the As and Sb host phases during soil reduction (laboratory incubation) using a sequential extraction procedure (fractions: loosely and strongly adsorbed, carbonates, easily reducible, reducible, oxidable and residual). The field results showed that, in the deeper, permanently water-saturated soil layers (<60 cm), the amounts of As and Sb were relatively low (As: 8 ± 2 µg·g−1 and Sb: 0.9 ± 0.2 µg·g−1) and related to the Fe content. In the periodically flooded upper soil layers (0–40 cm), the amounts of As and Sb were higher compared to the deeper layers (As: 36 ± 3 µg·g−1 and Sb: 1.14 ± 0.05 µg·g−1). The observed enrichment towards the surface was attributed to the higher content of organic matter (for Sb) and metalloids distribution among the easily reducible fraction (for As). The anoxic laboratory incubation of periodically waterlogged soil showed that, during soil reduction, As is largely mobilized from the easily reducible fraction and undergoes partial readsorption. Unlike As, Sb displayed a higher affinity for more stable soil components (e.g., reducible and residual fractions), which highlights its limited mobility in periodically waterlogged soil compared to As. The potentially mobilizable As and Sb estimated as the sum of the acetate-exchangeable, P-exchangeable, easily reducible and H2O2-organic fractions represent up to 83%, 69% and 53% of the total As and up to 53%, 44% and 54% of the total Sb at 0–20-cm, 40–60-cm and 90–110-cm depths, respectively. Thus, unpolluted soils may act as sources of As and Sb to aquatic environments and therefore have negative consequence on the downstream water quality.
Breast-Feeding from an Evolutionary Perspective
Authors: Brines Juan , Billeaud Claude
Published: October 2021

Lactation is the most critical period of mammal feeding given the compulsory dependence on milk of the offspring during a more or less extensive period following birth. This has also been the case for the human species until relatively recent times when heterologous milk processing has allowed the alternative of artificial lactation. The advantages and disadvantages of natural and artificial lactation (formula) have been widely discussed from the biological, psychological and cultural perspectives, without reaching a general agreement among the breastfeeding women themselves or among the health professionals concerned. On the subject of breastfeeding, the information available is enormous but as in other instances, the excess of it has often made it difficult to acquire objective knowledge on the matter that has hindered decision-making in specific circumstances. This situation is understandable given the diversity and the innumerable contingencies that the mother and health professionals must face in their natural and social (cultural) environments. To reduce these difficulties and taking into consideration the biological and cultural aspects involved in infant feeding, this article analyzes some aspects of the subject from the point of view of biological evolution as the mother-child dyad, mother-infant conflicts, in particular the conflict of weaning, late-onset primary lactase deficiency and the prevention from childhood of adult diseases. All of which allows to offer a testimony of gratitude and respect to women who have assumed the responsibility of breastfeeding their infants because without them the human species would not have existed.
Can a Healthcare Quality Improvement Initiative Reduce Disparity in the Treatment Delay among ST-Segment Elevation Myocardial Infarction Patients with Different Arrival Modes? Evidence from 33 General Hospitals and Their Anticipated Impact on Healthcare during Disasters and Public Health Emergencies
Authors: Li Na , Ma Junxiong , Zhou Shuduo , Dong Xuejie , Maimaitiming Mailikezhati , Jin Yinzi , Zheng Zhijie
Published: October 2021

(1) Background: Chest pain center accreditation has been associated with improved timelines of primary percutaneous coronary intervention (PCI) for ST-segment elevated myocardial infarction (STEMI). However, evidence from low- and middle-income regions was insufficient, and whether the sensitivity to improvements differs between walk-in and emergency medical service (EMS)-transported patients remained unclear. In this study, we aimed to examine the association of chest pain center accreditation status with door-to-balloon (D2B) time and the potential modification effect of arrival mode. (2) Methods: The associations were examined using generalized linear mixed models, and the effect modification of arrival mode was examined by incorporating an interaction term in the models. (3) Results: In 4186 STEMI patients, during and after accreditation were respectively associated with 65% (95% CI: 54%, 73%) and 71% (95% CI: 61%, 79%) reduced risk of D2B time being more than 90 min (using before accreditation as the reference). Decreases of 27.88 (95% CI: 19.57, 36.22) minutes and 26.55 (95% CI: 17.45, 35.70) minutes in D2B were also observed for the during and after accreditation groups, respectively. The impact of accreditation on timeline improvement was greater for EMS-transported patients than for walk-in patients. (4) Conclusions: EMS-transported patients were more sensitive to the shortened in-hospital delay associated with the initiative, which could exacerbate the existing disparity among patients with different arrival modes.
The Effects of Integrated Step Training into the Physical Education Curriculum of Children with Intellectual Disabilities
Authors: Wu Pei-Fung , Chang Yu-Wei , Chen Tai-Been , Chang Li-Ching
Published: October 2021

(1) Background: This study investigated the changes in step frequency, walking ability, and standing posture of students with intellectual disabilities by integrating step training into the students’ physical education curriculum; (2) Methods: The centroid formula was used to estimate the geometric center of the students’ bodies in video footage of each participant. Each participant’s stepping frequency per minute was recorded. After training, the teachers involved were interviewed regarding the participants’ everyday activities in school. Each step training session was recorded by two video cameras. Each step training session was observed and photographed by a senior physical education teacher with special education qualifications; (3) Results: The step training increased the stability of the participants’ body axes. The participants’ average steps per minute of the participants significantly improved from 24.200 ± 7.554 to 28.700 ± 8.629. Additionally, despite the students exhibiting anxious behavior (e.g., squeezing their hands and grasping at their clothes) at baseline, the frequency of these behaviors decreased significantly from week 4. Overall, the students’ daily activities, motivation, interpersonal interaction, self-confidence, and anxiety behaviors improved; (4) Conclusions: After the 8-week step program, the participants with intellectual disabilities improved their step frequency, movement stability, ability to perform daily activities, walking speed, motivation, interpersonal interaction, and self-confidence, and they exhibited a lower level of anxiety-related behaviors.
Tele-Yoga in Long Term Illness–Protocol for a Randomised Controlled Trial Including a Process Evaluation and Results from a Pilot Study
Authors: Strömberg Anna , Thylén Ingela , Orwelius Lotti , Klompstra Leonie , Jaarsma Tiny
Published: October 2021

Background: For people with long-term illness, debilitated by severe symptoms, it can be difficult to attend regular yoga classes. We have therefore developed a tele-health format of yoga that can be delivered in the home. The tele-yoga was co-designed with members of a patient-organisation, yoga-instructor, and IT-technician. It includes live-streamed group-yoga sessions twice a week and an app with instructions on how to self-perform yoga. Aim: To describe a study protocol for a randomised controlled trial (RCT) including a process evaluation and report on a pilot study evaluating method- and intervention-related components including feasibility, safety, and efficacy. Methods: Ten participants with heart failure aged between 41–76 years were randomised to tele-yoga (n = 5) or to the control group (n = 5). In the pilot study recruitment, enrolment, randomisation, and data collection of all outcomes including primary, secondary and process evaluation measures were tested according to the study protocol. Fidelity, adherence and acceptability to the tele-yoga group training and app use was determined. Safety was assessed by adverse events. Results: The pilot revealed that the methodological aspect of the protocol worked sufficiently in all aspects except for missing data in the physical test of two participants and one participant in the control-group that dropped out of the study at three months follow-up. The tele-yoga training did not lead to any adverse events or injuries, adherence of tele-yoga was sufficient according to preset limits. The tele-yoga intervention also showed some favourable trends of improvements in the composite-end point compared to the active control group. However, since data only was presented descriptively due to the small sample size, the impact of these trends should be interpreted carefully. Conclusion: Our pilot study showed promising results in feasibility, safety, and acceptability of the tele-yoga intervention. Some changes in the protocol have been made to decrease the risk of missing data in the measures of physical function and in the full-scale RCT now ongoing the results of the sample size calculation for 300 participants have included the estimated level of drop outs and missing data.
Evaluation of Gully Erosion Susceptibility Using a Maximum Entropy Model in the Upper Mkhomazi River Basin in South Africa
Authors: Bernini Alice , Bosino Alberto , Botha Greg A. , Maerker Michael
Published: October 2021

Soil erosion is one of the most challenging environmental issues in the world, causing unsustainable soil loss every year. In South Africa, several episodes of gully erosion have been documented and clearly linked to the presence of Quaternary colluvial deposits on the Drakensberg Mountain footslopes. The aim of this study was to identify and assess the triggering factors of gully erosion in the upper Mkhomazi River basin in KwaZulu-Natal, South Africa. We compiled a gully inventory map and applied remote sensing techniques as well as field surveys to validate the gully inventory. The gullies were subdivided into slope gullies and fluvial gullies. We derived susceptibility maps based on the spatial distribution of gully types to assess the most important driving factors. A stochastic modeling approach (MaxEnt) was applied, and the results showed two susceptibility maps within the spatial distribution of the gully erosion probability. To validate the MaxEnt model results, a subset of the existing inventory map was used. Additionally, by using areas with high susceptibilities, we were able to delineate previously unmapped colluvial deposits in the region. This predictive mapping tool can be applied to provide a theoretical basis for highlighting erosion-sensitive substrates to reduce the risk of expanding gully erosion.
Comparing Early Transcriptomic Responses of 18 Soybean (Glycine max) Genotypes to Iron Stress
Authors: Kohlhase Daniel R. , McCabe Chantal E. , Singh Asheesh K. , O’Rourke Jamie A. , Graham Michelle A.
Published: October 2021

Iron deficiency chlorosis (IDC) is an abiotic stress that negatively affects soybean (Glycine max [L.] Merr.) production. Much of our knowledge of IDC stress responses is derived from model plant species. Gene expression, quantitative trait loci (QTL) mapping, and genome-wide association studies (GWAS) performed in soybean suggest that stress response differences exist between model and crop species. Our current understanding of the molecular response to IDC in soybeans is largely derived from gene expression studies using near-isogenic lines differing in iron efficiency. To improve iron efficiency in soybeans and other crops, we need to expand gene expression studies to include the diversity present in germplasm collections. Therefore, we collected 216 purified RNA samples (18 genotypes, two tissue types [leaves and roots], two iron treatments [sufficient and deficient], three replicates) and used RNA sequencing to examine the expression differences of 18 diverse soybean genotypes in response to iron deficiency. We found a rapid response to iron deficiency across genotypes, most responding within 60 min of stress. There was little evidence of an overlap of specific differentially expressed genes, and comparisons of gene ontology terms and transcription factor families suggest the utilization of different pathways in the stress response. These initial findings suggest an untapped genetic potential within the soybean germplasm collection that could be used for the continued improvement of iron efficiency in soybean.
Histamine Increases Th2 Cytokine-Induced CCL18 Expression in Human M2 Macrophages
Authors: Mommert Susanne , Schaper Judith Tabea , Schaper-Gerhardt Katrin , Gutzmer Ralf , Werfel Thomas
Published: October 2021

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.
Nanoparticles for Targeted Brain Drug Delivery: What Do We Know?
Authors: Pinheiro Rúben G. R. , Coutinho Ana Joyce , Pinheiro Marina , Neves Ana Rute
Published: October 2021

The blood–brain barrier (BBB) is a barrier that separates the blood from the brain tissue and possesses unique characteristics that make the delivery of drugs to the brain a great challenge. To achieve this purpose, it is necessary to design strategies to allow BBB passage, in order to reach the brain and target the desired anatomic region. The use of nanomedicine has great potential to overcome this problem, since one can modify nanoparticles with strategic molecules that can interact with the BBB and induce uptake through the brain endothelial cells and consequently reach the brain tissue. This review addresses the potential of nanomedicines to treat neurological diseases by using nanoparticles specially developed to cross the BBB.
Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of Bordetella pertussis
Authors: Holubova Jana , Juhasz Attila , Masin Jiri , Stanek Ondrej , Jurnecka David , Osickova Adriana , Sebo Peter , Osicka Radim
Published: October 2021

The whooping cough agent, Bordetella pertussis, secretes an adenylate cyclase toxin–hemolysin (CyaA, ACT, or AC-Hly) that catalyzes the conversion of intracellular ATP to cAMP and through its signaling annihilates the bactericidal activities of host sentinel phagocytes. In parallel, CyaA permeabilizes host cells by the formation of cation-selective membrane pores that account for the hemolytic activity of CyaA. The pore-forming activity contributes to the overall cytotoxic effect of CyaA in vitro, and it has previously been proposed to synergize with the cAMP-elevating activity in conferring full virulence on B. pertussis in the mouse model of pneumonic infection. CyaA primarily targets myeloid phagocytes through binding of their complement receptor 3 (CR3, integrin αMβ2, or CD11b/CD18). However, with a reduced efficacy, the toxin can promiscuously penetrate and permeabilize the cell membrane of a variety of non-myeloid cells that lack CR3 on the cell surface, including airway epithelial cells or erythrocytes, and detectably intoxicates them by cAMP. Here, we used CyaA variants with strongly and selectively enhanced or reduced pore-forming activity that, at the same time, exhibited a full capacity to elevate cAMP concentrations in both CR3-expressing and CR3-non-expressing target cells. Using B. pertussis mutants secreting such CyaA variants, we show that a selective enhancement of the cell-permeabilizing activity of CyaA does not increase the overall virulence and lethality of pneumonic B. pertussis infection of mice any further. In turn, a reduction of the cell-permeabilizing activity of CyaA did not reduce B. pertussis virulence any importantly. These results suggest that the phagocyte-paralyzing cAMP-elevating capacity of CyaA prevails over the cell-permeabilizing activity of CyaA that appears to play an auxiliary role in the biological activity of the CyaA toxin in the course of B. pertussis infections in vivo.
Recent Progress in Rice Broad-Spectrum Disease Resistance
Authors: Liu Zhiquan , Zhu Yujun , Shi Huanbin , Qiu Jiehua , Ding Xinhua , Kou Yanjun
Published: October 2021

Rice is one of the most important food crops in the world. However, stable rice production is constrained by various diseases, in particular rice blast, sheath blight, bacterial blight, and virus diseases. Breeding and cultivation of resistant rice varieties is the most effective method to control the infection of pathogens. Exploitation and utilization of the genetic determinants of broad-spectrum resistance represent a desired way to improve the resistance of susceptible rice varieties. Recently, researchers have focused on the identification of rice broad-spectrum disease resistance genes, which include R genes, defense-regulator genes, and quantitative trait loci (QTL) against two or more pathogen species or many isolates of the same pathogen species. The cloning of broad-spectrum disease resistance genes and understanding their underlying mechanisms not only provide new genetic resources for breeding broad-spectrum rice varieties, but also promote the development of new disease resistance breeding strategies, such as editing susceptibility and executor R genes. In this review, the most recent advances in the identification of broad-spectrum disease resistance genes in rice and their application in crop improvement through biotechnology approaches during the past 10 years are summarized.
The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer
Authors: Kłos Patrycja , Dabravolski Siarhei A.
Published: October 2021

Inflammatory bowel disease (IBD) is one of the leading gut chronic inflammation disorders, especially prevalent in Western countries. Recent research suggests that mitochondria play a crucial role in IBD development and progression to the more severe disease—colorectal cancer (CRC). In this review, we focus on the role of mitochondrial mutations and dysfunctions in IBD and CRC. In addition, main mitochondria-related molecular pathways involved in IBD to CRC transition are discussed. Additionally, recent publications dedicated to mitochondria-targeted therapeutic approaches to cure IBD and prevent CRC progression are discussed.
Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease
Authors: Czapski Grzegorz A. , Strosznajder Joanna B.
Published: October 2021

The physiological balance between excitation and inhibition in the brain is significantly affected in Alzheimer’s disease (AD). Several neuroactive compounds and their signaling pathways through various types of receptors are crucial in brain homeostasis, among them glutamate and γ-aminobutyric acid (GABA). Activation of microglial receptors regulates the immunological response of these cells, which in AD could be neuroprotective or neurotoxic. The novel research approaches revealed the complexity of microglial function, including the interplay with other cells during neuroinflammation and in the AD brain. The purpose of this review is to describe the role of several proteins and multiple receptors on microglia and neurons, and their involvement in a communication network between cells that could lead to different metabolic loops and cell death/survival. Our review is focused on the role of glutamatergic, GABAergic signaling in microglia–neuronal cross-talk in AD and neuroinflammation. Moreover, the significance of AD-related neurotoxic proteins in glutamate/GABA-mediated dialogue between microglia and neurons was analyzed in search of novel targets in neuroprotection, and advanced pharmacological approaches.
Involvement of GPR17 in Neuronal Fibre Outgrowth
Authors: Braune Max , Scherf Nico , Heine Claudia , Sygnecka Katja , Pillaiyar Thanigaimalai , Parravicini Chiara , Heimrich Bernd , Abbracchio Maria P. , Müller Christa E. , Franke Heike
Published: October 2021

Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.
Ezrin Peptide Therapy from HIV to COVID: Inhibition of Inflammation and Amplification of Adaptive Anti-Viral Immunity
Authors: Holms Rupert D. , Ataullakhanov Ravshan I.
Published: October 2021

Human Ezrin Peptides (HEPs) are inhibitors of expression of IL-6 and other inflammatory cytokines, amplifiers of adaptive B cell and T cell immunity and enhancers of tissue repair. The mutation stable C-terminus of HIV gp120, mimics 69% of the “Hep-receptor”, a zipped α-helical structure in the middle of the α domain of human ezrin protein. Synthetic peptides homologous to the Hep-receptor of ezrin of five to fourteen amino acids, activate anti-viral immunity against a wide range of viruses (HIV, HCV, herpes, HPV, influenza and other human respiratory viruses). Human Ezrin Peptide One (HEP1) TEKKRRETVEREKE (brand name Gepon, registered for human use in Russia from 2001) is a successful treatment for opportunistic infections in HIV-infected patients. That treats HEP1and prevents mucosal candidiasis, herpes zoster outbreaks and infection-induced chronic diarrhea. There are clinical publications in Russian on the successful treatments of chronic recurrent vaginal candidiasis, acute and chronic enterocolitis and dysbacteriosis, which are accompanied by normalization of the mucosal microbiome, and the decline or disappearance of inflammation. HEP1 is also an effective treatment and prevention for recurrent inflammation and ulceration in the stomach, duodenum and colon. HEP1 and RepG3 GEKKRRETVEREGG (a derivative of HEP1) have been used successfully as an inhaled spray peptide solution to treat a small number of human volunteers with mild-to-moderate COVID, resulting from SARS-CoV-2 infection, based on earlier successes in treating acute viral respiratory disease with inflammatory complications. Ezrin peptides seem to correct a dysregulation of innate immune responses to SARS-CoV-2. They are also adjuvants of B cell adaptive immunity and increase antibody titres, resulting in protection from lethal virus infection of mice. In a clinical study in Moscow, orally administered HEP1 was shown to enhance antibody-titres produced in response to hepatitis-B vaccination. These very preliminary but promising results with ezrin peptide treatment of COVID must be replicated in large-scale randomised placebo controlled clinical studies, to be verified.
Biological Therapies in the Treatment of Cancer—Update and New Directions
Authors: Papież Monika A. , Krzyściak Wirginia
Published: October 2021

Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies.
IL-15 Prevents Renal Fibrosis by Inhibiting Collagen Synthesis: A New Pathway in Chronic Kidney Disease?
Authors: Devocelle Aurore , Lecru Lola , Ferlicot Sophie , Bessede Thomas , Candelier Jean-Jacques , Giron-Michel Julien , François Hélène
Published: October 2021

Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15’s renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.
Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction
Authors: Jeong Jin Young , Na Ki Ryang , Shin Jin Ah , Suh Kwang-Sun , Kim Jwa-Jin , Lee Kang Wook , Choi Dae Eun
Published: October 2021

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1flox/flox (wild-type (WT)) group, a CRIF1flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-β and α-smooth muscle actin staining, and Masson’s trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury.
Salivary Adipokine and Cytokine Levels as Potential Markers for the Development of Obesity and Metabolic Disorders
Authors: Zyśk Beata , Ostrowska Lucyna , Smarkusz-Zarzecka Joanna
Published: October 2021

Currently, the number of people suffering from obesity is increasing worldwide. In addition, the disease is affecting younger individuals. Therefore, it is essential to search for new diagnostic methods and markers for early assessment of the risk of obesity, metabolic disorders, and other comorbidities. The discovery of the secretory function of adipose tissue and coexistence of low-grade chronic inflammation with obesity set a new direction in this disease diagnosis using the assessment of the concentration of inflammatory markers secreted by adipose tissue. The aim of this review was to determine, based on previous findings, whether saliva can be useful in the diagnosis of obesity and its early metabolic complications and whether it can be an alternative diagnostic material to serum.
Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice
Authors: Kim Ha-Neui , Richardson Kimberly K. , Krager Kimberly J. , Ling Wen , Simmons Pilar , Allen Antino R. , Aykin-Burns Nukhet
Published: October 2021

Space is a high-stress environment. One major risk factor for the astronauts when they leave the Earth’s magnetic field is exposure to ionizing radiation from galactic cosmic rays (GCR). Several adverse changes occur in mammalian anatomy and physiology in space, including bone loss. In this study, we assessed the effects of simplified GCR exposure on skeletal health in vivo. Three months following exposure to 0.5 Gy total body simulated GCR, blood, bone marrow and tissue were collected from 9 months old male mice. The key findings from our cell and tissue analysis are (1) GCR induced femoral trabecular bone loss in adult mice but had no effect on spinal trabecular bone. (2) GCR increased circulating osteoclast differentiation markers and osteoclast formation but did not alter new bone formation or osteoblast differentiation. (3) Steady-state levels of mitochondrial reactive oxygen species, mitochondrial and non-mitochondrial respiration were increased without any changes in mitochondrial mass in pre-osteoclasts after GCR exposure. (4) Alterations in substrate utilization following GCR exposure in pre-osteoclasts suggested a metabolic rewiring of mitochondria. Taken together, targeting radiation-mediated mitochondrial metabolic reprogramming of osteoclasts could be speculated as a viable therapeutic strategy for space travel induced bone loss.
The Role of APOE and NF-κB in Alzheimer’s Disease
Authors: Davies Don A.
Published: October 2021

Apolipoprotein E (APOE) has three different isoforms, with APOE4 carriers representing a major risk factor for the development of Alzheimer’s disease (AD). AD is the most common form of dementia, and is a relentlessly progressive disorder that afflicts the aged, characterized by severe memory loss. Presently, AD does not have a cure, increasing the urgency for the development of novel therapeutics for the prevention/treatment of AD. The APOE4 isoform is associated with many pathological mechanisms, such as increased neuroinflammation and a reduction in β-amyloid (Aβ) clearance. The accumulation of Aβ plaques in the brain is a hallmark of AD. The presence of APOE4 can increase neuroinflammation via overactivation of the nuclear factor kappa B (NF-κB) pathway. The NF-κB pathway is a family of transcription factors involved with regulating over 400 genes involved with inflammation. AD is associated with sustained inflammation and an overactivation of the NF-κB pathway. Therefore, targeting the APOE4 isoform and suppressing the NF-κB pathway using anti-inflammatory compounds may result in the development of novel therapeutics for the prevention/treatment of AD.
Host Acceptance and Plant Resistance: A Comparative Behavioral Study of Myzus persicae and Acyrthosiphon pisum
Authors: Jhou Yi-Syuan , Poovendhan Sushanthi , Huang Li-Hsin , Tsai Chi-Wei
Published: October 2021

Aphids are prominent phloem-feeding insect pests. Myzus persicae and Acyrthosiphon pisum are generalist and specialist species, respectively. In this study, these two aphid species were used to investigate host acceptance and plant resistance to aphid feeding. M.persicae survived and reproduced on rape (Brassica rapa), but few individuals (9%) survived on faba bean (Vicia faba). A.pisum survived and reproduced on faba bean, but no A.pisum survived on rape. The probing and feeding behavior of M. persicae and A. pisum on rape and faba bean was examined using an electrical penetration graph (EPG) technique. The results demonstrated the feeding preferences of these two aphid species. The EPG results suggest that the resistance of faba bean to M. persicae and that of rape to A. pisum are likely residing in the phloem and mesophyll tissues, respectively. Due to the distinct probing and feeding behaviors, specialist and generalist aphids would have different impacts on the epidemiology of plant viral diseases. The findings can be applied to the management of viral diseases transmitted by specialist or generalist aphids in crop production.
Volatiles Induced from Hypolepis punctata (Dennstaedtiaceae) by Herbivores Attract Sclomina erinacea (Hemiptera: Reduviidae): Clear Evidence of Indirect Defense in Fern
Authors: Huang Kerui , Shang Hui , Zhou Qiong , Wang Yun , Shen Hui , Yan Yuehong
Published: October 2021

Plants have evolved various self-defense mechanisms against insect feeding. There are many reports regarding both direct and indirect defense mechanisms in seed-plant. However, only direct defenses on ferns were considered and the indirect defense mechanism has never been reported. In this study, it was observed that the fern Hypolepis punctata can attract the assassin bug Sclomina erinacea in the field. We collected and analyzed volatiles from H. punctata healthy individuals and the ones wounded by Bertula hadenalis, using dynamic headspace and GC-MS. We recorded the electroantennogram responses of antennae of S. erinacea to different standards of volatile compounds identified from the GC-MS analysis. We also analyzed the behavior of male and female S. erinacea adults in response to volatiles collected from H. punctata using a Y-tube olfactometer. The results showed that a number of volatile compounds were produced when the fern was damaged by B. hadenalis. Electroantennography and Y-tube olfactometer results showed that some herbivore-induced volatiles and volatiles from undamaged leaves could attract S. erinacea. Our research suggests that H. punctata can attract insect predators by releasing herbivory-induced volatile organic compounds, and for the first time we found ferns may also have indirect defense mechanisms using volatile organic compounds.
Macular Structure–Function Relationships of All Retinal Layers in Primary Open-Angle Glaucoma Assessed by Microperimetry and 8 × 8 Posterior Pole Analysis of OCT
Authors: Garcia-Medina Jose Javier , Rotolo Maurilia , Rubio-Velazquez Elena , Pinazo-Duran Maria Dolores , del-Rio-Vellosillo Monica
Published: October 2021

Purpose: The aim of this study is too correlate the sensitivity and thickness values of intraretinal layers at macula in healthy eyes and primary open-angle glaucoma (POAG) eyes. Methods: The thickness of different intraretinal segmentations was estimated by means of optical coherence tomography (OCT) Spectralis (Heidelberg, Engineering, Inc., Heidelberg, Germany) with the posterior pole analysis program 8 × 8 in 91 eyes from 91 patients (60 with glaucoma and 31 healthy patients). Macular sensitivity was also measured with an MP-1 microperimeter (Nidek Instruments, Inc Padova, Italy) with a customized, 36-stimulus pattern adjusted to an anatomical correspondence with the OCT grid. Correlations were calculated by using Spearman’s rho and the results were represented in color maps. Results: Significant structure–function correlations were much more frequent in the glaucoma group than in control group. In general terms, associations were positive for inner retinal layers but negative correlations were also found for the inner nuclear layer and outer retinal layer in glaucoma. Conclusions: In general terms, significant structure–function correlations for different intraretinal layers are higher and wider in POAG eyes than in healthy eyes. Inner and outer retinal layers behave differently in terms of the structure–function relationship in POAG as assessed by microperimetry and OCT.
Microvascular and Structural Alterations of the Macula in Early to Moderate Glaucoma: An Optical Coherence Tomography-Angiography Study
Authors: Lever Mael , Glaser Moritz , Chen Ying , Halfwassen Christian , Unterlauft Jan Darius , Bechrakis Nikolaos E. , Böhm Michael R. R.
Published: October 2021

In glaucoma, macular optical coherence tomography (OCT) typically shows a thinning of the three inner segments and OCT-angiography (OCTA) a reduction of the vascular density (VD). It is still unclear if glaucoma directly affects macular VD. This retrospective study included 31 glaucoma patients of early and moderate stage (GS1, GS2, Mills et al.) and 39 healthy individuals. Macular segments’ thickness and superficial and deep plexus vascular density (VD) were obtained using spectral-domain OCT and OCTA, respectively. One-way analysis of variance (ANOVA) was used to compare healthy controls and glaucoma patients according to their glaucoma stage. Using correlation analyses, the association between glaucoma and either OCT or OCTA parameters was evaluated. A glaucoma stage-stratified linear regression analysis was then performed. Inner macular segment and whole retinal thickness were reduced in GS1 and GS2 patients compared to healthy controls (e.g., ganglion cell layer GCL: controls: 47.9 ± 7.4, GS1: 45.8 ± 5.1, GS2: 30.6 ± 9.4, ANOVA: p < 0.0001). Regarding OCTA-parameters, the VD of both segmentation levels was reduced in glaucoma patients, particularly when comparing GS2 patients with controls (superficial plexus: p = 0.004) and GS2 with GS1 (p = 0.0008). Linear regression revealed an association between these parameters and the presence of glaucoma (for superior plexus: R2 = 0.059, p = 0.043). Finally, a correlation between macular segment thickness and VD was observed, but with a strength increasing with glaucoma severity (GCL and superior plexus VD: controls: R2 = 0.23, GS1 R2 = 0.40, GS2 R2 = 0.76). Despite the glaucoma-independent correlation between macular segment thickness and VD, disease severity strengthens this correlation. This consideration suggests that glaucoma directly influences OCT and OCTA parameters individually.