bluuebunny/crossref_metadata_2025 huggingface dataset:
An Oxalate Transporter Gene, AtOT, Enhances Aluminum Tolerance in Arabidopsis thaliana by Regulating Oxalate Efflux
Authors: Yang Zongming , Zhao Pingjuan , Luo Xuehua , Peng Wentao , Liu Zifan , Xie Guishui , Wang Mengyue , An Feng
Published: February 2023

Secretion and efflux of oxalic acid from roots is an important aluminum detoxification mechanism for various plants; however, how this process is completed remains unclear. In this study, the candidate oxalate transporter gene AtOT, encoding 287 amino acids, was cloned and identified from Arabidopsis thaliana. AtOT was upregulated in response to aluminum stress at the transcriptional level, which was closely related to aluminum treatment concentration and time. The root growth of Arabidopsis was inhibited after knocking out AtOT, and this effect was amplified by aluminum stress. Yeast cells expressing AtOT enhanced oxalic acid resistance and aluminum tolerance, which was closely correlated with the secretion of oxalic acid by membrane vesicle transport. Collectively, these results underline an external exclusion mechanism of oxalate involving AtOT to enhance oxalic acid resistance and aluminum tolerance.
Increased Intracellular Free Zinc Has Pleiotropic Effects on Doxorubicin-Induced Cytotoxicity in hiPCS-CMs Cells
Authors: Rudolf Kamil , Rudolf Emil
Published: February 2023

(1) the mechanisms and outcomes of doxorubicin (DOX)-dependent toxicity upon changed intracellular zinc (Zn) concentrations in the cardiomyocytes obtained from human-induced pluripotent stem cells (hiPCS-CMs) were investigated; (2) cells exposed to the DOX were pretreated or cotreated with zinc pyrythione (ZnPyr) and various cellular endpoints and mechanisms were analyzed via cytometric methods; (3) both DOX concentrations (0.3 and 1 µM) induced a concentration-dependent loss of viability, an activation of autophagy, cell death, and the appearance of senescence. These phenotypes were preceded by an oxidative burst, DNA damage, and a loss of mitochondrial and lysosomal integrity. Furthermore, in DOX-treated cells, proinflammatory and stress kinase signaling (in particular, JNK and ERK) were upregulated upon the loss of free intracellular Zn pools. Increased free Zn concentrations proved to have both inhibitory and stimulatory effects on the investigated DOX-related molecular mechanisms, as well as on signaling pathways on the resulting cell fates; and (4) free intracellular Zn pools, their status, and their elevation might have, in a specific context, a pleiotropic impact upon DOX-dependent cardiotoxicity.
Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma
Authors: Krebs Fanny Seraphine , Moura Bianca , Missiaglia Edoardo , Aedo-Lopez Veronica , Michielin Olivier , Tsantoulis Petros , Bisig Bettina , Trimech Mounir , Zoete Vincent , Homicsko Krisztian
Published: February 2023

The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.
Effect of Chain Extending Cross-Linkers on the Disintegration Behavior of Composted PBAT/PLA Blown Films
Authors: Azevedo Juliana V. C. , Hausnerova Berenika , Möginger Bernhard , Sopik Tomas
Published: February 2023

A biodegradable blend of PBAT—poly(butylene adipate-co-terephthalate)—and PLA—poly(lactic acid)—for blown film extrusion was modified with four multi-functional chain extending cross-linkers (CECL). The anisotropic morphology introduced during film blowing affects the degradation processes. Given that two CECL increased the melt flow rate (MFR) of tris(2,4-di-tert-butylphenyl)phosphite (V1) and 1,3-phenylenebisoxazoline (V2) and the other two reduced it (aromatic polycarbodiimide (V3) and poly(4,4-dicyclohexylmethanecarbodiimide) (V4)), their compost (bio-)disintegration behavior was investigated. It was significantly altered with respect to the unmodified reference blend (REF). The disintegration behavior at 30 and 60 °C was investigated by determining changes in mass, Young’s moduli, tensile strengths, elongations at break and thermal properties. In order to quantify the disintegration behavior, the hole areas of blown films were evaluated after compost storage at 60 °C to calculate the kinetics of the time dependent degrees of disintegration. The kinetic model of disintegration provides two parameters: initiation time and disintegration time. They quantify the effects of the CECL on the disintegration behavior of the PBAT/PLA compound. Differential scanning calorimetry (DSC) revealed a pronounced annealing effect during storage in compost at 30 °C, as well as the occurrence of an additional step-like increase in the heat flow at 75 °C after storage at 60 °C. The disintegration consists of processes which affect amorphous and crystalline phase of PBAT in different manner that cannot be understood by a hydrolytic chain degradation only. Furthermore, gel permeation chromatography (GPC) revealed molecular degradation only at 60 °C for the REF and V1 after 7 days of compost storage. The observed losses of mass and cross-sectional area seem to be attributed more to mechanical decay than to molecular degradation for the given compost storage times.
Liver Organoids as an In Vitro Model to Study Primary Liver Cancer
Authors: De Siervi Silvia , Turato Cristian
Published: February 2023

Primary liver cancers (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the leading causes of cancer-related mortality worldwide. Bi-dimensional in vitro models are unable to recapitulate the key features of PLC; consequently, recent advancements in three-dimensional in vitro systems, such as organoids, opened up new avenues for the development of innovative models for studying tumour’s pathological mechanisms. Liver organoids show self-assembly and self-renewal capabilities, retaining essential aspects of their respective in vivo tissue and allowing modelling diseases and personalized treatment development. In this review, we will discuss the current advances in the field of liver organoids focusing on existing development protocols and possible applications in regenerative medicine and drug discovery.
Frailty and the Interactions between Skeletal Muscle, Bone, and Adipose Tissue-Impact on Cardiovascular Disease and Possible Therapeutic Measures
Authors: Soto María Elena , Pérez-Torres Israel , Rubio-Ruiz María Esther , Cano-Martínez Agustina , Manzano-Pech Linaloe , Guarner-Lans Verónica
Published: February 2023

Frailty is a global health problem that impacts clinical practice. It is complex, having a physical and a cognitive component, and it is the result of many contributing factors. Frail patients have oxidative stress and elevated proinflammatory cytokines. Frailty impairs many systems and results in a reduced physiological reserve and increased vulnerability to stress. It is related to aging and to cardiovascular diseases (CVD). There are few studies on the genetic factors of frailty, but epigenetic clocks determine age and frailty. In contrast, there is genetic overlap of frailty with cardiovascular disease and its risk factors. Frailty is not yet considered a risk factor for CVD. It is accompanied by a loss and/or poor functioning of muscle mass, which depends on fiber protein content, resulting from the balance between protein breakdown and synthesis. Bone fragility is also implied, and there is a crosstalk between adipocytes, myocytes, and bone. The identification and assessment of frailty is difficult, without there being a standard instrument to identify or treat it. Measures to prevent its progression include exercises, as well as supplementing the diet with vitamin D and K, calcium, and testosterone. In conclusion, more research is needed to better understand frailty and to avoid complications in CVD.
Mechanism of Action of Peripheral Nerve Stimulation for Chronic Pain: A Narrative Review
Authors: Ong Sio Lady Christine , Hom Brian , Garg Shuchita , Abd-Elsayed Alaa
Published: February 2023

The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been growing evidence for the use of peripheral nerve stimulation (PNS) for treating a myriad of chronic pain conditions such as limb mononeuropathies, nerve entrapments, peripheral nerve injuries, phantom limb pain, complex regional pain syndrome, back pain, and even fibromyalgia. The ease of placement of a minimally invasive electrode via percutaneous approach in the close vicinity of the nerve and the ability to target various nerves have led to its widespread use and compliance. While most of the mechanism behind its role in neuromodulation is largely unknown, the gate control theory proposed by Melzack and Wall in the 1960s has been the mainstay for understanding its mechanism of action. In this review article, the authors performed a literature review to discuss the mechanism of action of PNS and discuss its safety and usefulness in treating chronic pain. The authors also discuss current PNS devices available in the market today.
Intestinal Transplant Immunology and Intestinal Graft Rejection: From Basic Mechanisms to Potential Biomarkers
Authors: Rumbo Martin , Oltean Mihai
Published: February 2023

Intestinal transplantation (ITx) remains a lifesaving option for patients suffering from irreversible intestinal failure and complications from total parenteral nutrition. Since its inception, it became obvious that intestinal grafts are highly immunogenic, due to their high lymphoid load, the abundance in epithelial cells and constant exposure to external antigens and microbiota. This combination of factors and several redundant effector pathways makes ITx immunobiology unique. To this complex immunologic situation, which leads to the highest rate of rejection among solid organs (>40%), there is added the lack of reliable non-invasive biomarkers, which would allow for frequent, convenient and reliable rejection surveillance. Numerous assays, of which several were previously used in inflammatory bowel disease, have been tested after ITx, but none have shown sufficient sensibility and/or specificity to be used alone for diagnosing acute rejection. Herein, we review and integrate the mechanistic aspects of graft rejection with the current knowledge of ITx immunobiology and summarize the quest for a noninvasive biomarker of rejection.
Breaking the Gingival Barrier in Periodontitis
Authors: Vitkov Ljubomir , Singh Jeeshan , Schauer Christine , Minnich Bernd , Krunić Jelena , Oberthaler Hannah , Gamsjaeger Sonja , Herrmann Martin , Knopf Jasmin , Hannig Matthias
Published: February 2023

The break of the epithelial barrier of gingiva has been a subject of minor interest, albeit playing a key role in periodontal pathology, transitory bacteraemia, and subsequent systemic low-grade inflammation (LGI). The significance of mechanically induced bacterial translocation in gingiva (e.g., via mastication and teeth brushing) has been disregarded despite the accumulated knowledge of mechanical force effects on tight junctions (TJs) and subsequent pathology in other epithelial tissues. Transitory bacteraemia is observed as a rule in gingival inflammation, but is rarely observed in clinically healthy gingiva. This implies that TJs of inflamed gingiva deteriorate, e.g., via a surplus of lipopolysaccharide (LPS), bacterial proteases, toxins, Oncostatin M (OSM), and neutrophil proteases. The inflammation-deteriorated gingival TJs rupture when exposed to physiological mechanical forces. This rupture is characterised by bacteraemia during and briefly after mastication and teeth brushing, i.e., it appears to be a dynamic process of short duration, endowed with quick repair mechanisms. In this review, we consider the bacterial, immune, and mechanical factors responsible for the increased permeability and break of the epithelial barrier of inflamed gingiva and the subsequent translocation of both viable bacteria and bacterial LPS during physiological mechanical forces, such as mastication and teeth brushing.
Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy
Authors: Iacobucci Ilaria , Hay Mele Bruno , Cozzolino Flora , Monaco Vittoria , Cimmaruta Chiara , Monti Maria , Andreotti Giuseppina , Monticelli Maria
Published: February 2023

Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.
Photodynamic Effects with 5-Aminolevulinic Acid on Cytokines and Exosomes in Human Peripheral Blood Mononuclear Cells from Patients with Crohn’s Disease
Authors: Espeland Kristian , Kleinauskas Andrius , Juzenas Petras , Darvekar Sagar , Vasovic Vlada , Warloe Trond , Christensen Eidi , Jahnsen Jørgen , Peng Qian
Published: February 2023

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) which is the precursor of the photosensitizer protoporphyrin IX (PpIX) is an available treatment for several diseases. ALA-PDT induces the apoptosis and necrosis of target lesions. We have recently reported the effects of ALA-PDT on cytokines and exosomes of human healthy peripheral blood mononuclear cells (PBMCs). This study has investigated the ALA-PDT-mediated effects on PBMC subsets from patients with active Crohn’s disease (CD). No effects on lymphocyte survival after ALA-PDT were observed, although the survival of CD3−/CD19+ B-cells seemed slightly reduced in some samples. Interestingly, ALA-PDT clearly killed monocytes. The subcellular levels of cytokines and exosomes associated with inflammation were widely downregulated, which is consistent with our previous findings in PBMCs from healthy human subjects. These results suggest that ALA-PDT may be a potential treatment candidate for CD and other immune-mediated diseases.
Psoriatic Resolved Skin Epidermal Keratinocytes Retain Disease-Residual Transcriptomic and Epigenomic Profiles
Authors: Ghaffarinia Ameneh , Ayaydin Ferhan , Póliska Szilárd , Manczinger Máté , Bolla Beáta Szilvia , Flink Lili Borbála , Balogh Fanni , Veréb Zoltán , Bozó Renáta , Szabó Kornélia , Bata-Csörgő Zsuzsanna , Kemény Lajos
Published: February 2023

The disease-residual transcriptomic profile (DRTP) within psoriatic healed/resolved skin and epidermal tissue-resident memory T (TRM) cells have been proposed to be crucial for the recurrence of old lesions. However, it is unclear whether epidermal keratinocytes are involved in disease recurrence. There is increasing evidence regarding the importance of epigenetic mechanisms in the pathogenesis of psoriasis. Nonetheless, the epigenetic changes that contribute to the recurrence of psoriasis remain unknown. The aim of this study was to elucidate the role of keratinocytes in psoriasis relapse. The epigenetic marks 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) were visualized using immunofluorescence staining, and RNA sequencing was performed on paired never-lesional and resolved epidermal and dermal compartments of skin from psoriasis patients. We observed diminished 5-mC and 5-hmC amounts and decreased mRNA expression of the ten-eleven translocation (TET) 3 enzyme in the resolved epidermis. SAMHD1, C10orf99, and AKR1B10: the highly dysregulated genes in resolved epidermis are known to be associated with pathogenesis of psoriasis, and the DRTP was enriched in WNT, TNF, and mTOR signaling pathways. Our results suggest that epigenetic changes detected in epidermal keratinocytes of resolved skin may be responsible for the DRTP in the same regions. Thus, the DRTP of keratinocytes may contribute to site-specific local relapse.
Genetic Risk Assessment of Nonsyndromic Cleft Lip with or without Cleft Palate by Linking Genetic Networks and Deep Learning Models
Authors: Kang Geon , Baek Seung-Hak , Kim Young Ho , Kim Dong-Hyun , Park Ji Wan
Published: February 2023

Recent deep learning algorithms have further improved risk classification capabilities. However, an appropriate feature selection method is required to overcome dimensionality issues in population-based genetic studies. In this Korean case–control study of nonsyndromic cleft lip with or without cleft palate (NSCL/P), we compared the predictive performance of models that were developed by using the genetic-algorithm-optimized neural networks ensemble (GANNE) technique with those models that were generated by eight conventional risk classification methods, including polygenic risk score (PRS), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGBoost), and deep-learning-based artificial neural network (ANN). GANNE, which is capable of automatic input SNP selection, exhibited the highest predictive power, especially in the 10-SNP model (AUC of 88.2%), thus improving the AUC by 23% and 17% compared to PRS and ANN, respectively. Genes mapped with input SNPs that were selected by using a genetic algorithm (GA) were functionally validated for risks of developing NSCL/P in gene ontology and protein–protein interaction (PPI) network analyses. The IRF6 gene, which is most frequently selected via GA, was also a major hub gene in the PPI network. Genes such as RUNX2, MTHFR, PVRL1, TGFB3, and TBX22 significantly contributed to predicting NSCL/P risk. GANNE is an efficient disease risk classification method using a minimum optimal set of SNPs; however, further validation studies are needed to ensure the clinical utility of the model for predicting NSCL/P risk.
Expression of Non-T Cell Activation Linker (NTAL) in Jurkat Cells Negatively Regulates TCR Signaling: Potential Role in Rheumatoid Arthritis
Authors: Narbona-Sánchez Isaac , Pérez-Linaza Alba , Serrano-García Isabel , Vico-Barranco Inmaculada , Fernández-Aguilar Luis M. , Poveda-Díaz José L. , Sánchez del Pino María J. , Medina-Varo Fermín , Arbulo-Echevarria Mikel M. , Aguado Enrique
Published: February 2023

T lymphocytes are key players in adaptive immune responses through the recognition of peptide antigens through the T Cell Receptor (TCR). After TCR engagement, a signaling cascade is activated, leading to T cell activation, proliferation, and differentiation into effector cells. Delicate control of activation signals coupled to the TCR is needed to avoid uncontrolled immune responses involving T cells. It has been previously shown that mice deficient in the expression of the adaptor NTAL (Non-T cell activation linker), a molecule structurally and evolutionarily related to the transmembrane adaptor LAT (Linker for the Activation of T cells), develop an autoimmune syndrome characterized by the presence of autoantibodies and enlarged spleens. In the present work we intended to deepen investigation into the negative regulatory functions of the NTAL adaptor in T cells and its potential relationship with autoimmune disorders. For this purpose, in this work we used Jurkat cells as a T cell model, and we lentivirally transfected them to express the NTAL adaptor in order to analyze the effect on intracellular signals associated with the TCR. In addition, we analyzed the expression of NTAL in primary CD4+ T cells from healthy donors and Rheumatoid Arthritis (RA) patients. Our results showed that NTAL expression in Jurkat cells decreased calcium fluxes and PLC-γ1 activation upon stimulation through the TCR complex. Moreover, we showed that NTAL was also expressed in activated human CD4+ T cells, and that the increase of its expression was reduced in CD4+ T cells from RA patients. Our results, together with previous reports, suggest a relevant role for the NTAL adaptor as a negative regulator of early intracellular TCR signaling, with a potential implication in RA.
Genome-Wide Investigation of the NAC Transcription Factor Family in Apocynum venetum Revealed Their Synergistic Roles in Abiotic Stress Response and Trehalose Metabolism
Authors: Huang Xiaoyu , Qiu Xiaojun , Wang Yue , Abubakar Aminu Shehu , Chen Ping , Chen Jikang , Chen Kunmei , Yu Chunming , Wang Xiaofei , Gao Gang , Zhu Aiguo
Published: February 2023

NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) are one of the most prominent plant-specific TF families and play essential roles in plant growth, development and adaptation to abiotic stress. Although the NAC gene family has been extensively characterized in many species, systematic analysis is still relatively lacking in Apocynum venetum (A. venetum). In this study, 74 AvNAC proteins were identified from the A. venetum genome and were classified into 16 subgroups. This classification was consistently supported by their gene structures, conserved motifs and subcellular localizations. Nucleotide substitution analysis (Ka/Ks) showed the AvNACs to be under the influence of strong purifying selection, and segmental duplication events were found to play the dominant roles in the AvNAC TF family expansion. Cis-elements analysis demonstrated that the light-, stress-, and phytohormone-responsive elements being dominant in the AvNAC promoters, and potential TFs including Dof, BBR-BPC, ERF and MIKC_MADS were visualized in the TF regulatory network. Among these AvNACs, AvNAC58 and AvNAC69 exhibited significant differential expression in response to drought and salt stresses. The protein interaction prediction further confirmed their potential roles in the trehalose metabolism pathway with respect to drought and salt resistance. This study provides a reference for further understanding the functional characteristics of NAC genes in the stress-response mechanism and development of A. venetum.
Zebrafish HERC7c Acts as an Inhibitor of Fish IFN Response
Authors: Li Yi-Lin , Gong Xiu-Ying , Qu Zi-Ling , Zhao Xiang , Dan Cheng , Sun Hao-Yu , An Li-Li , Gui Jian-Fang , Zhang Yi-Bing
Published: February 2023

In humans, four small HERCs (HERC3-6) exhibit differential degrees of antiviral activity toward HIV-1. Recently we revealed a novel member HERC7 of small HERCs exclusively in non-mammalian vertebrates and varied copies of herc7 genes in distinct fish species, raising a question of what is the exact role for a certain fish herc7 gene. Here, a total of four herc7 genes (named HERC7a–d sequentially) are identified in the zebrafish genome. They are transcriptionally induced by a viral infection, and detailed promoter analyses indicate that zebrafish herc7c is a typical interferon (IFN)-stimulated gene. Overexpression of zebrafish HERC7c promotes SVCV (spring viremia of carp virus) replication in fish cells and concomitantly downregulates cellular IFN response. Mechanistically, zebrafish HERC7c targets STING, MAVS, and IRF7 for protein degradation, thus impairing cellular IFN response. Whereas the recently-identified crucian carp HERC7 has an E3 ligase activity for the conjugation of both ubiquitin and ISG15, zebrafish HERC7c only displays the potential to transfer ubiquitin. Considering the necessity for timely regulation of IFN expression during viral infection, these results together suggest that zebrafish HERC7c is a negative regulator of fish IFN antiviral response.
Expression Dynamics of CA IX Epitope in Cancer Cells under Intermittent Hypoxia Correlates with Extracellular pH Drop and Cell Killing by Ureido-Sulfonamide CA IX Inhibitors
Authors: Sufian Md. Abu , Zamanova Sabina , Shabana Ahmed M. , Kemp Brianna , Mondal Utpal K. , Supuran Claudiu T. , Ilies Marc A.
Published: February 2023

Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in tumor biochemistry, we investigated the expression dynamics of CA IX in normoxia, hypoxia and intermittent hypoxia, which are typical conditions experienced by tumor cells in aggressive carcinomas. We correlated the CA IX epitope expression dynamics with extracellular pH acidification and with viability of CA IX-expressing cancer cells upon treatment with CA IX inhibitors (CAIs) in colon HT-29, breast MDA-MB-231 and ovarian SKOV-3 tumor cell models. We observed that the CA IX epitope expressed under hypoxia by these cancer cells is retained in a significant amount upon reoxygenation, probably to preserve their proliferation ability. The extracellular pH drop correlated well with the level of CA IX expression, with the intermittent hypoxic cells showing a similar pH drop to fully hypoxic ones. All cancer cells showed higher sensitivity to CA IX inhibitors (CAIs) under hypoxia as compared to normoxia. The tumor cell sensitivity to CAIs under hypoxia and intermittent hypoxia were similar and higher than in normoxia and appeared to be correlated with the lipophilicity of the CAI.
Separase and Roads to Disengage Sister Chromatids during Anaphase
Authors: Konecna Marketa , Abbasi Sani Soodabeh , Anger Martin
Published: February 2023

Receiving complete and undamaged genetic information is vital for the survival of daughter cells after chromosome segregation. The most critical steps in this process are accurate DNA replication during S phase and a faithful chromosome segregation during anaphase. Any errors in DNA replication or chromosome segregation have dire consequences, since cells arising after division might have either changed or incomplete genetic information. Accurate chromosome segregation during anaphase requires a protein complex called cohesin, which holds together sister chromatids. This complex unifies sister chromatids from their synthesis during S phase, until separation in anaphase. Upon entry into mitosis, the spindle apparatus is assembled, which eventually engages kinetochores of all chromosomes. Additionally, when kinetochores of sister chromatids assume amphitelic attachment to the spindle microtubules, cells are finally ready for the separation of sister chromatids. This is achieved by the enzymatic cleavage of cohesin subunits Scc1 or Rec8 by an enzyme called Separase. After cohesin cleavage, sister chromatids remain attached to the spindle apparatus and their poleward movement on the spindle is initiated. The removal of cohesion between sister chromatids is an irreversible step and therefore it must be synchronized with assembly of the spindle apparatus, since precocious separation of sister chromatids might lead into aneuploidy and tumorigenesis. In this review, we focus on recent discoveries concerning the regulation of Separase activity during the cell cycle.
Tumor Necrosis Factor Family Members and Myocardial Ischemia-Reperfusion Injury: State of the Art and Therapeutic Implications
Authors: Galeone Antonella , Grano Maria , Brunetti Giacomina
Published: February 2023

Ischemic heart disease is the principal cause of death worldwide and clinically manifests as myocardial infarction (MI), stable angina, and ischemic cardiomyopathy. Myocardial infarction is defined as an irreversible injury due to severe and prolonged myocardial ischemia inducing myocardial cell death. Revascularization is helpful in reducing loss of contractile myocardium and improving clinical outcome. Reperfusion rescues myocardium from cell death but also induces an additional injury called ischemia-reperfusion injury. Multiple mechanisms are involved in ischemia-reperfusion injury, such as oxidative stress, intracellular calcium overload, apoptosis, necroptosis, pyroptosis, and inflammation. Various members of the tumor necrosis factor family play a key role in myocardial ischemia-reperfusion injury. In this article, the role of TNFα, CD95L/CD95, TRAIL, and the RANK/RANKL/OPG axis in the regulation of myocardial tissue damage is reviewed together with their potential use as a therapeutic target.
Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective
Authors: Zulkefli Nabilah , Che Zahari Che Nur Mazadillina , Sayuti Nor Hafiza , Kamarudin Ammar Akram , Saad Norazalina , Hamezah Hamizah Shahirah , Bunawan Hamidun , Baharum Syarul Nataqain , Mediani Ahmed , Ahmed Qamar Uddin , Ismail Ahmad Fahmi Harun , Sarian Murni Nazira
Published: February 2023

Wounds are considered to be a serious problem that affects the healthcare sector in many countries, primarily due to diabetes and obesity. Wounds become worse because of unhealthy lifestyles and habits. Wound healing is a complicated physiological process that is essential for restoring the epithelial barrier after an injury. Numerous studies have reported that flavonoids possess wound-healing properties due to their well-acclaimed anti-inflammatory, angiogenesis, re-epithelialization, and antioxidant effects. They have been shown to be able to act on the wound-healing process via expression of biomarkers respective to the pathways that mainly include Wnt/β-catenin, Hippo, Transforming Growth Factor-beta (TGF-β), Hedgehog, c-Jun N-Terminal Kinase (JNK), NF-E2-related factor 2/antioxidant responsive element (Nrf2/ARE), Nuclear Factor Kappa B (NF-κB), MAPK/ERK, Ras/Raf/MEK/ERK, phosphatidylinositol 3-kinase (PI3K)/Akt, Nitric oxide (NO) pathways, etc. Hence, we have compiled existing evidence on the manipulation of flavonoids towards achieving skin wound healing, together with current limitations and future perspectives in support of these polyphenolic compounds as safe wound-healing agents, in this review.
Linking Histone Methylation States and hsp Transcriptional Regulation in Thermo-Tolerant and Thermo-Susceptible A. mellifera L. Subspecies in Response to Heat Stress
Authors: Alattal Yehya Z. , Alghamdi Ahmad A.
Published: February 2023

Genetic and epigenetic responses to environmental cues of worker honeybees mediate hsp synthesis, a key mechanism to tolerate high ambient temperatures in Apis mellifera. In this study, the chromatin immunoprecipitation assay followed by qPCR were used to determine alterations in histone methylation states (H3K27me2, H3K27me3, H3K4me2, and H3K4me3) associated with hsp/hsc/trx in A. m. jemenetica (thermo-tolerant subspecies) and A. m. carnica (thermo-susceptible subspecies) after heat treatment. The results revealed significant changes in enrichment folds of histone methylation states associated with hsp/hsc/trx. Indeed, the enrichment of H3K27me2 decreased strongly in response to heat stress. Changes in histone methylation states were significantly higher in A. m. carnica samples compared to A. m. jemenitica samples. Our study provides a new perception on linking histone post-translational methylation as an epigenetic mechanism of gene regulation with hsp/hsc/trx in A. mellifera subspecies exposed to heat stress.
Population Dynamics of Insect Pests and Beneficials on Different Snap Bean Cultivars
Authors: Li Yinping , Mbata George , Simmons Alvin
Published: February 2023

Snap bean is an important crop in the United States. Insecticides are commonly used against pests on snap bean, but many pests have developed resistance to the insecticides and beneficials are threatened by the insecticides. Therefore, host plant resistance is a sustainable alternative. Population dynamics of insect pests and beneficials were assessed on 24 snap bean cultivars every week for six weeks. The lowest number of sweetpotato whitefly (Bemisia tabaci) eggs was observed on cultivar ‘Jade’, and the fewest nymphs were found on cultivars ‘Gold Mine’, ‘Golden Rod’, ‘Long Tendergreen’, and ‘Royal Burgundy’. The numbers of potato leafhopper (Empoasca fabae) and tarnished plant bug (Lygus lineolaris) adults were the lowest on cultivars ‘Greencrop’ and ‘PV-857′. The highest numbers of adults were found in Week 1 (25 days following plant emergence) for B. tabaci and Mexican bean beetle (Epilachna varivestis); Week 3 for cucumber beetle, kudzu bug (Megacopta cribraria), and E. fabae; Weeks 3 and 4 for thrips; Week 4 for L. lineolaris; and Weeks 5 and 6 for bees. Temperature and relative humidity correlated with B. tabaci, E. varivestis, bee, and predator ladybird beetle populations. These results provide valuable information on the integrated pest management of snap beans.
Comparison of Morphological Characteristics of Antennae and Antennal Sensilla among Four Species of Bumblebees (Hymenoptera: Apidae)
Authors: Ren Chang-Shi , Chang Zhi-Min , Zu Zhi-Yun , Han Lei , Chen Xiang-Sheng , Long Jian-Kun
Published: February 2023

Bumblebees, as pollinators, play an important role in maintaining natural and agricultural ecosystems. Antennae with sensilla of bumblebees as social insects have essential effects in foraging, nest searching, courting, and mating, and are different in species and sexes. Previous studies on the morphology of antennae and sensilla in bumblebees have been limited to a few species and a single caste. To better understand how bumblebees detect and receive the chemical signal from nectariferous plants and foraging behavior, the morphology of antennae with sensilla, including the antennal length, and type, distribution, and number of antennal sensilla in four species, Bombus atripes, Bombus breviceps, Bombus flavescens, and Bombus terrestris was compared by scanning electron microscopy (SEM) herein. The total antennal length of queens are the longest and workers are the shortest in three castes, and in four species the longest of the total antennal length among three castes all are in B. flavescens, which is significantly longer than other species (p < 0.05) and the length of the scape in queens and workers are both longer than males, significantly different in queens (p < 0.05), and not significantly different in workers (p > 0.05), and the length of flagellums in females are not always shorter than males, of which the length of flagellms in queens of B. flavescens are significantly longer than males (p < 0.05), and the length of pedicel and all flagellomeres varies among species and castes. A total of 13 major types of sensilla in total were observed, including trichodea sensilla (TS A-E), placodea sensilla (PS A-B), basiconica sensilla (BaS), coeloconica sensilla (COS A-B), chaetic sensilla (CS A-B), and Böhm sensilla (BS), of which chaetic sensilla B (CS B), only observed in females of B. atripes, was firstly reported in Apidae. Moreover, the number of all sensilla was the most in males, the least was in workers, the number of sensilla varies within castes and species. Furthermore, the morphological characteristics of antennae and the potential functions of sensilla are discussed.
Biogeographical Patterns of Earwigs in Italy
Authors: Fattorini Simone
Published: February 2023

Placed in the center of the Mediterranean biodiversity hotspot, Italy plays a central role for the study of Europe’s biogeography. In this paper, the influence of climatic, spatial, and historical factors on current patterns of variation in earwig species richness and composition is investigated. The Italian earwig fauna is mainly composed of species which are either widely distributed in Europe and the Palearctic region or that are endemic to the Alps and the Apennines. Variation in species richness does not follow any obvious geographical patterns, but a positive influence of precipitation on richness is consistent with earwig preferences for humid climates. European mainland territories did not contribute substantially to the current biodiversity of Italian earwigs, which explains the lack of a distinct peninsula effect, although a southward decrease in similarity with the central European fauna was observed. However, southern areas did not exert a pivotal role during Pleistocene glaciations in determining current patterns of species richness. Variation in species composition among Italian regions can be mostly explained by geographical proximity, while climatic differences and historical (paleogeographical and paleoecological) events seem to have played a minor role. However, the isolation of ancient earwig stocks on Italian mountains led to the origin of a relatively large number of endemics, which makes the Italian earwig fauna one of the richest in Europe.
New Mitogenomes of the Polypedilum Generic Complex (Diptera: Chironomidae): Characterization and Phylogenetic Implications
Authors: Zhang Dan , He Fei-Xiang , Li Xue-Bo , Aishan Zhulidezi , Lin Xiao-Long
Published: February 2023

Mitochondrial genomics, as a useful marker for phylogenetics and systematics of organisms, are important for molecular biology studies. The phylogenetic relationships of the Polypedilum generic complex remains controversial, due to lack taxonomy and molecular information. In this study, we newly sequenced mitogenomes of 14 species of the Polypedilum generic complex. Coupled with three recently published sequences, we analyzed the nucleotide composition, sequence length, and evolutionary rate of this generic complex. The control region showed the highest AT content. The evolution rate of protein coding genes was as follows: ATP8 > ND6 > ND5 > ND3 > ND2 > ND4L > ND4 > COX1 > ND1 > CYTB > APT6 > COX2 > COX3. We reconstructed the phylogenetic relationships among the genera within the Polypedilum generic complex based on 19 mitochondrial genomes (seventeen ingroups and two outgroups), using Bayesian Inference (BI) and Maximum Likelihood (ML) methods for all databases. Phylogenetic analysis of 19 mitochondrial genomes demonstrated that the Endochironomus + Synendotendipes was sister to Phaenopsectra + Sergentia.
The Global Burden of Glaucoma: Findings from the Global Burden of Disease 2019 Study and Predictions by Bayesian Age–Period–Cohort Analysis
Authors: Lin Yi , Jiang Bingcai , Cai Yuanqing , Luo Wangdu , Zhu Xiaomin , Lin Qianyi , Tang Min , Li Xiangji , Xie Lin
Published: February 2023

This study aims to report the most up-to-date information about the global disease burden of glaucoma from 1990 to 2019 and to forecast trends in the next few years. Publicly available data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were used in this study. The prevalence and disability-adjusted life years (DALYs) of glaucoma from 1990 to 2019 were reported. Finally, trends in the years following 2019 were predicted by Bayesian age–period–cohort (BAPC) models. We showed that, globally, the number of prevalent cases was 3,881,624 [95% uncertainty interval (UI): 3,301,963 to 4,535,045] in 1990 and increased to 7,473,400 (95% UI: 6,347,183 to 8,769,520) in 2019, while the age-standardized prevalence rate decreased from 111.92 [95% uncertainty interval (UI): 94.76 to 130.28 per 100,000] in 1990 to 94.68 (95% UI: 80.42 to 110.87 per 100,000) in 2019. The DALY number of glaucoma increased between 1990 and 2019, from 442,182 (95% UI: 301,827 to 626,486) in 1990 to 748,308 (95% UI: 515,636 to 1,044,667) in 2019. There was a significantly negative association between the sociodemographic index (SDI) and age-standardized DALY rates. The BAPC showed that the age-standardized DALY rate is predicted to decrease gradually in both males and females over the next few years. In summary, from 1990 to 2019, the global burden of glaucoma increased and the age-standardized DALY rate is predicted to decrease in the next few years. With the largest burden of glaucoma found in low-SDI regions, clinical diagnosis and treatment in such areas are more challenging and may warrant more attention.
Does Endometriosis Impact the Composition of Follicular Fluid in IL6 and AMH? A Case-Control Study
Authors: Kacem-Berjeb Khadija , Braham Marouen , Massoud Cyrine Ben , Hannachi Hela , Hamdoun Manel , Chtourou Sana , Debbabi Linda , Bouyahia Maha , Fadhlaoui Anis , Zhioua Fethi , Feki Anis , Chakroun Nozha , Bahri Olfa
Published: February 2023

Objective: The aim of this study was to compare follicular liquid levels of IL6 and AMH in women with and without endometriosis and to evaluate their potential impact on ICSI outcomes. Materials and Methods: It is a prospective case-control study conducted on 25 women with proven endometriosis and 50 patients diagnosed with other causes of infertility. All these patients were candidates for ICSI cycles. Their follicular fluid was collected at the time of oocyte retrieval and used to evaluate IL-6 and AMH titers by electro-chemiluminescent immunoassay (Cobas e411-Roche). Results: The IL-6 levels in follicular fluid were higher in the endometriosis group than in the control group (152.3 vs. 19.9 pg/mL; p = 0.02). The median level for AMH was 2.2 ± 1.88 ng/mL with no statistical difference between the two groups (2.2 vs. 2.7 ng/mL, p = 0.41). No significant correlation between the follicular IL6 and AMH levels was observed. Conclusions: The oocyte quality seems to be preserved in patients with endometriosis with the adequate response to ovarian stimulation. High levels of follicular IL6 are in accordance with the inflammatory phenomenon of the disease; however, this increase has no impact on ICSI outcomes.
Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Is a Promising Signature to Predict Prognosis and Therapies for Hepatocellular Carcinoma (HCC)
Authors: Chen Yuyan , Xia Senzhe , Zhang Lu , Qin Xueqian , Zhu Zhengyi , Ma Tao , Lu Shushu , Chen Jing , Shi Xiaolei , Ren Haozhen
Published: February 2023

Background: The roles of mitochondria and the endoplasmic reticulum (ER) in the progression of hepatocellular carcinoma (HCC) are well established. However, a special domain that regulates the close contact between the ER and mitochondria, known as the mitochondria-associated endoplasmic reticulum membrane (MAM), has not yet been investigated in detail in HCC. Methods: The TCGA-LIHC dataset was only used as a training set. In addition, the ICGC and several GEO datasets were used for validation. Consensus clustering was applied to test the prognostic value of the MAM-associated genes. Then, the MAM score was constructed using the lasso algorithm. In addition, uncertainty of clustering in single-cell RNA-seq data using a gene co-expression network (AUCell) was used for the detection of the MAM scores in various cell types. Then, CellChat analysis was applied for comparing the interaction strength between the different MAM score groups. Further, the tumor microenvironment score (TME score) was calculated to compare the prognostic values, the correlation with the other HCC subtypes, tumor immune infiltration landscape, genomic mutations, and copy number variations (CNV) of different subgroups. Finally, the response to immune therapy and sensitivity to chemotherapy were also determined. Results: First, it was observed that the MAM-associated genes could differentiate the survival rates of HCC. Then, the MAM score was constructed and validated using the TCGA and ICGC datasets, respectively. The AUCell analysis indicated that the MAM score was higher in the malignant cells. In addition, enrichment analysis demonstrated that malignant cells with a high MAM score were positively correlated with energy metabolism pathways. Furthermore, the CellChat analysis indicated that the interaction strength was reinforced between the high-MAM-score malignant cells and T cells. Finally, the TME score was constructed, which demonstrated that the HCC patients with high MAM scores/low TME scores tend to have a worse prognosis and high frequency of genomic mutations, while those with low MAM scores/high TME scores were more likely to have a better response to immune therapy. Conclusions: MAM score is a promising index for determining the need for chemotherapy, which reflects the energy metabolic pathways. A combination of the MAM score and TME score could be a better indicator to predict prognosis and response to immune therapy.
Kidney Biopsy in Pregnant Women with Glomerular Diseases: Focus on Lupus Nephritis
Authors: Moroni Gabriella , Calatroni Marta , Donato Beatriz , Ponticelli Claudio
Published: February 2023

Despite significant improvements of renal and obstetrical management, pregnancies in women with glomerular diseases and with lupus nephritis continue to be associated with increased complications both for the mother and the fetus as compared to those of pregnancies in healthy women. To reduce the risk of these complications, planning pregnancy in a phase of stable remission of the underlining disease is necessary. A kidney biopsy is an important event in any phase of pregnancy. A kidney biopsy can be of help during counselling before pregnancy in cases of incomplete remission of the renal manifestations. In these situations, histological data may differentiate active lesions that require the reinforcement of therapy from chronic irreversible lesions that may increase the risk of complications. In pregnant women, a kidney biopsy can identify new-onset systemic lupus erythematous (SLE) and necrotizing or primitive glomerular diseases and distinguish them from other, more common complications. Increasing proteinuria, hypertension, and the deterioration of kidney function during pregnancy may be either due to a reactivation of the underlying disease or to pre-eclampsia. The results of the kidney biopsy suggest the need to initiate an appropriate treatment, allowing the progression of the pregnancy and the fetal viability or the anticipation of delivery. Data from the literature suggest avoiding a kidney biopsy beyond 28 weeks of gestation to minimize the risks associated with the procedure vs. the risk of preterm delivery. In case of the persistence of renal manifestations after delivery in women with a diagnosis of pre-eclampsia, a renal kidney assessment allows the final diagnosis and guides the therapy.