bluuebunny/crossref_metadata_2025 huggingface dataset:
Marker-Assisted Selection in Breeding for Fruit Trait Improvement: A Review
Authors: De Mori Gloria , Cipriani Guido
Published: May 2023

Breeding fruit species is time-consuming and expensive. With few exceptions, trees are likely the worst species to work with in terms of genetics and breeding. Most are characterized by large trees, long juvenile periods, and intensive agricultural practice, and environmental variability plays an important role in the heritability evaluations of every single important trait. Although vegetative propagation allows for the production of a significant number of clonal replicates for the evaluation of environmental effects and genotype × environment interactions, the spaces required for plant cultivation and the intensity of work necessary for phenotypic surveys slow down the work of researchers. Fruit breeders are very often interested in fruit traits: size, weight, sugar and acid content, ripening time, fruit storability, and post-harvest practices, among other traits relevant to each individual species. The translation of trait loci and whole-genome sequences into diagnostic genetic markers that are effective and affordable for use by breeders, who must choose genetically superior parents and subsequently choose genetically superior individuals among their progeny, is one of the most difficult tasks still facing tree fruit geneticists. The availability of updated sequencing techniques and powerful software tools offered the opportunity to mine tens of fruit genomes to find out sequence variants potentially useful as molecular markers. This review is devoted to analysing what has been the role of molecular markers in assisting breeders in selection processes, with an emphasis on the fruit traits of the most important fruit crops for which examples of trustworthy molecular markers have been developed, such as the MDo.chr9.4 marker for red skin colour in apples, the CCD4-based marker CPRFC1, and LG3_13.146 marker for flesh colour in peaches, papayas, and cherries, respectively.
Effectiveness of TaDreb-B1 and 1-FEH w3 KASP Markers in Spring and Winter Wheat Populations for Marker-Assisted Selection to Improve Drought Tolerance
Authors: Eltaher Shamseldeen , Hashem Mostafa , Ahmed Asmaa A. M. , Baenziger P. Stephen , Börner Andreas , Sallam Ahmed
Published: May 2023

Due to the advances in DNA markers, kompetitive allele-specific PCR (KASP) markers could accelerate breeding programs and genetically improve drought tolerance. Two previously reported KASP markers, TaDreb-B1 and 1-FEH w3, were investigated in this study for the marker-assisted selection (MAS) of drought tolerance. Two highly diverse spring and winter wheat populations were genotyped using these two KASP markers. The same populations were evaluated for drought tolerance at seedling (drought stress) and reproductive (normal and drought stress) growth stages. The single-marker analysis revealed a high significant association between the target allele of 1-FEH w3 and drought susceptibility in the spring population, while the marker–trait association was not significant in the winter population. The TaDreb-B1 marker did not have any highly significant association with seedling traits, except the sum of leaf wilting in the spring population. For field experiments, SMA revealed very few negative and significant associations between the target allele of the two markers and yield traits under both conditions. The results of this study revealed that the use of TaDreb-B1 provided better consistency in improving drought tolerance than 1-FEH w3.
Structural Insights into Phosphorylation-Mediated Polymerase Function Loss for DNA Polymerase β Bound to Gapped DNA
Authors: Srivastava Amit , Idriss Haitham , Homouz Dirar
Published: May 2023

DNA polymerase β is a member of the X-family of DNA polymerases, playing a critical role in the base excision repair (BER) pathway in mammalian cells by implementing the nucleotide gap-filling step. In vitro phosphorylation of DNA polymerase β with PKC on S44 causes loss in the enzyme’s DNA polymerase activity but not single-strand DNA binding. Although these studies have shown that single-stranded DNA binding is not affected by phosphorylation, the structural basis behind the mechanism underlying phosphorylation-induced activity loss remains poorly understood. Previous modeling studies suggested phosphorylation of S44 was sufficient to induce structural changes that impact the enzyme’s polymerase function. However, the S44 phosphorylated-enzyme/DNA complex has not been modeled so far. To address this knowledge gap, we conducted atomistic molecular dynamics simulations of pol β complexed with gapped DNA. Our simulations, which used explicit solvent and lasted for microseconds, revealed that phosphorylation at the S44 site, in the presence of Mg ions, induced significant conformational changes in the enzyme. Specifically, these changes led to the transformation of the enzyme from a closed to an open structure. Additionally, our simulations identified phosphorylation-induced allosteric coupling between the inter-domain region, suggesting the existence of a putative allosteric site. Taken together, our results provide a mechanistic understanding of the conformational transition observed due to phosphorylation in DNA polymerase β interactions with gapped DNA. Our simulations shed light on the mechanisms of phosphorylation-induced activity loss in DNA polymerase β and reveal potential targets for the development of novel therapeutics aimed at mitigating the effects of this post-translational modification.
Genome-Wide Identification and Functional Analysis of the AP2/ERF Transcription Factor Family in Citrus Rootstock under Waterlogging Stress
Authors: He Wen , Luo Liang , Xie Rui , Chai Jiufeng , Wang Hao , Wang Yan , Chen Qing , Wu Zhiwei , Yang Shaofeng , Li Mengyao , Lin Yuanxiu , Zhang Yunting , Luo Ya , Zhang Yong , Tang Haoru , Wang Xiaorong
Published: May 2023

Citrus plants are sensitive to waterlogging, and the roots are the first plant organ affected by hypoxic stress. The AP2/ERF (APETALA2/ethylene-responsive element binding factors) can modulate plant growth and development. However, the information on AP2/ERF genes in citrus rootstock and their involvement in waterlogging conditions is limited. Previously, a rootstock cultivar, Citrus junos cv. Pujiang Xiangcheng was found to be highly tolerant to waterlogging stress. In this study, a total of 119 AP2/ERF members were identified in the C. junos genome. Conserved motif and gene structure analyses indicated the evolutionary conservation of PjAP2/ERFs. Syntenic gene analysis revealed 22 collinearity pairs among the 119 PjAP2/ERFs. The expression profiles under waterlogging stress showed differential expression of PjAP2/ERFs, of which, PjERF13 was highly expressed in both root and leaf. Furthermore, the heterologous expression of PjERF13 significantly enhanced the tolerance of transgenic tobacco to waterlogging stress. The overexpression of PjERF13 decreased the oxidative damage in the transgenic plants by reducing the H2O2 and MDA contents and increasing the antioxidant enzyme activities in the root and leaf. Overall, the current study provided basic information on the AP2/ERF family in the citrus rootstock and uncovered their potential function in positively regulating the waterlogging stress response.
Thiopurines Analogues with Additional Ring: Synthesis, Spectroscopic Properties, and Anticancer Potency
Authors: Krancewicz Katarzyna , Nowicka-Bauer Karolina , Fiedorowicz Katarzyna , Marciniak Bronislaw , Taras-Goslinska Katarzyna
Published: May 2023

Purine scaffolds constitute a starting point for the synthesis of numerous chemotherapeutics used in treating cancer, viruses, parasites, as well as bacterial and fungal infections. In this work, we synthesized a group of guanosine analogues containing an additional five-membered ring and a sulfur atom at the C-9 position. The spectral, photophysical, and biological properties of the synthesized compounds were investigated. The spectroscopic studies revealed that a combination of the thiocarbonyl chromophore and the tricyclic structure of guanine analogues shifts the absorption region above 350 nm, allowing for selective excitation when present in biological systems. Unfortunately, due to the low fluorescence quantum yield, this process cannot be used to monitor the presence of these compounds in cells. The synthesized compounds were evaluated for their effect on the viability of human cervical carcinoma (HeLa) and mouse fibroblast (NIH/3T3) cells. It was found that all of them display anticancer activity. In vitro studies were preceded by in silico ADME and PASS analyses, which confirmed that the designed compounds are promising candidates for anticancer agents.
Aging Changes the Efficacy of Central Urocortin 2 to Induce Weight Loss in Rats
Authors: Kovács Dóra K. , Eitmann Szimonetta , Berta Gergely , Kormos Viktória , Gaszner Balázs , Pétervári Erika , Balaskó Márta
Published: May 2023

Middle-aged obesity and aging cachexia present healthcare challenges. Central responsiveness to body-weight-reducing mediators, e.g., to leptin, changes during aging in a way, which may promote middle-aged obesity and aging cachexia. Leptin is connected to urocortin 2 (Ucn2), an anorexigenic and hypermetabolic member of the corticotropin family. We aimed to study the role of Ucn2 in middle-aged obesity and aging cachexia. The food intake, body weight and hypermetabolic responses (oxygen consumption, core temperature) of male Wistar rats (3, 6, 12 and 18 months) were tested following intracerebroventricular injections of Ucn2. Following one central injection, Ucn2-induced anorexia lasted for 9 days in the 3-month, 14 days in the 6-month and 2 days in the 18-month group. Middle-aged 12-month rats failed to show anorexia or weight loss. Weight loss was transient (4 days) in the 3-month, 14 days in the 6-month and slight but long-lasting in the 18-month rats. Ucn2-induced hypermetabolism and hyperthermia increased with aging. The age-dependent changes in the mRNA expression of Ucn2 detected by RNAscope in the paraventricular nucleus correlated with the anorexigenic responsiveness. Our results show that age-dependent changes in Ucn2 may contribute to middle-aged obesity and aging cachexia. Ucn2 shows potential in the prevention of middle-aged obesity.
Spatial Distribution and Temporal Dynamics of Candidatus Liberibacter Asiaticus in Different Stages of Embryos, Nymphs and Adults of Diaphorina citri
Authors: Nian Xiaoge , Wu Shujie , Li Jiayun , Luo Yaru , He Jielan , Tan Shijian , Wang Desen , Cen Yijing , He Yurong
Published: May 2023

Huanglongbing, a globally devastating citrus disease, is associated with Candidatus Liberibacter asiaticus (CLas) and is mainly transmitted by Diaphorina citri. Verification of the distribution and dynamics of CLas in D. citri is critical to understanding CLas transmitted by vectors in nature. Here, the distribution and titers of CLas in different sexes and tissues of D. citri adults were investigated by fluorescence in-situ hybridization (FISH) and quantitative real-time PCR (qRT-PCR). Results showed that CLas had widespread distribution in the brain, salivary glands, digestive system, and reproductive system of both females and males, indicating a systemic infection of CLas in D. citri. Moreover, CLas fluorescence intensity and titers were significantly increased in both the digestive system and the female reproductive system with development and there was a marked decreased in both the salivary glands and the male brain, but there was no significant change in the female brain or the male reproductive system. Furthermore, the distribution and dynamics of CLas in embryos and nymphs were investigated. CLas was observed in all laid eggs and subsequent first–second-instar nymphs, indicating that a high percentage of embryos and nymphs resulting from infected D. citri mothers were infected with CLas.
Single-Dose Treatment with Rapamycin Preserves Post-Ischemic Cardiac Function through Attenuation of Fibrosis and Inflammation in Diabetic Rabbit
Authors: Samidurai Arun , Saravanan Manu , Ockaili Ramzi , Kraskauskas Donatas , Lau Suet Ying Valerie , Kodali Varun , Ramasamy Shakthi , Bhoopathi Karthikeya , Nair Megha , Roh Sean K. , Kukreja Rakesh C. , Das Anindita
Published: May 2023

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial ischemia/reperfusion (I/R) injury in diabetic rabbits. Diabetic rabbits (DM) were subjected to 45 min of ischemia and 10 days of reperfusion by inflating/deflating a previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before the onset of reperfusion. Post-I/R left ventricular (LV) function was assessed by echocardiography and fibrosis was evaluated by picrosirius red staining. Treatment with RAPA preserved LV ejection fraction and reduced fibrosis. Immunoblot and real-time PCR revealed that RAPA treatment inhibited several fibrosis markers (TGF-β, Galectin-3, MYH, p-SMAD). Furthermore, immunofluorescence staining revealed the attenuation of post-I/R NLRP3-inflammasome formation with RAPA treatment as shown by reduced aggregation of apoptosis speck-like protein with a caspase recruitment domain and active-form of caspase-1 in cardiomyocytes. In conclusion, our study suggests that acute reperfusion therapy with RAPA may be a viable strategy to preserve cardiac function with the alleviation of adverse post-infarct myocardial remodeling and inflammation in diabetic patients.
Analgesic Effects of Fisetin, Peimine, Astaxanthin, Artemisinin, Bardoxolone Methyl and 740 Y-P and Their Influence on Opioid Analgesia in a Mouse Model of Neuropathic Pain
Authors: Ciapała Katarzyna , Rojewska Ewelina , Pawlik Katarzyna , Ciechanowska Agata , Mika Joanna
Published: May 2023

Treatment of neuropathic pain remains a challenge for modern medicine due to the insufficiently understood molecular mechanisms of its development and maintenance. One of the most important cascades that modulate the nociceptive response is the family of mitogen-activated protein (MAP) kinases and phosphatidylinositol-3-kinase (PI3K), as well as nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this study was to determine the effect of nonselective modulators of MAP kinases—fisetin (ERK1/2 and NFκB inhibitor, PI3K activator), peimine (MAPK inhibitor), astaxanthin (MAPK inhibitor, Nrf2 activator) and artemisinin (MAPK inhibitor, NFκB activator), as well as bardoxolone methyl (selective activator of Nrf2) and 740 Y-P (selective activator of PI3K)—in mice with peripheral neuropathy and to compare their antinociceptive potency and examine their effect on analgesia induced by opioids. The study was performed using albino Swiss male mice that were exposed to chronic constriction injury of the sciatic nerve (CCI model). Tactile and thermal hypersensitivity was measured using von Frey and cold plate tests, respectively. Single doses of substances were administered intrathecally on day 7 after CCI. Among the tested substances, fisetin, peimine, and astaxanthin effectively diminished tactile and thermal hypersensitivity in mice after CCI, while artemisinin did not exhibit analgesic potency in this model of neuropathic pain. Additionally, both of the activators tested, bardoxolone methyl and 740 Y-P, also showed analgesic effects after intrathecal administration in mice exposed to CCI. In the case of astaxanthin and bardoxolone methyl, an increase in analgesia after combined administration with morphine, buprenorphine, and/or oxycodone was observed. Fisetin and peimine induced a similar effect on tactile hypersensitivity, where analgesia was enhanced after administration of morphine or oxycodone. In the case of 740 Y-P, the effects of combined administration with each opioid were observed only in the case of thermal hypersensitivity. The results of our research clearly indicate that substances that inhibit all three MAPKs provide pain relief and improve opioid effectiveness, especially if they additionally block NF-κB, such as peimine, inhibit NF-κB and activate PI3K, such as fisetin, or activate Nrf2, such as astaxanthin. In light of our research, Nrf2 activation appears to be particularly beneficial. The abovementioned substances bring promising results, and further research on them will broaden our knowledge regarding the mechanisms of neuropathy and perhaps contribute to the development of more effective therapy in the future.
Carrier-Mediated Process of Putrescine Elimination at the Rat Blood–Retinal Barrier
Authors: Tega Yuma , Kubo Yoshiyuki , Miura Hiroaki , Ri Kairi , Tomise Ayaka , Akanuma Shin-ichi , Hosoya Ken-ichi
Published: May 2023

Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood–retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [14C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [3H]putrescine and [14C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [3H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [3H]Putrescine transport was significantly reduced under Na+-free, Cl−-free, and K+-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [3H]putrescine uptake, and CTL1 knockdown significantly reduced [3H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.
Soluble ST2 in Patients with Carotid Artery Stenosis—Association with Plaque Morphology and Long-Term Outcome
Authors: Stojkovic Stefan , Kampf Stephanie , Harkot Olesya , Nackenhorst Maja , Brekalo Mira , Huber Kurt , Hengstenberg Christian , Neumayer Christoph , Wojta Johann , Demyanets Svitlana
Published: May 2023

Interleukin (IL-33) and the ST2 receptor are implicated in the pathogenesis of atherosclerosis. Soluble ST2 (sST2), which negatively regulates IL-33 signaling, is an established biomarker in coronary artery disease and heart failure. Here we aimed to investigate the association of sST2 with carotid atherosclerotic plaque morphology, symptom presentation, and the prognostic value of sST2 in patients undergoing carotid endarterectomy. A total of 170 consecutive patients with high-grade asymptomatic or symptomatic carotid artery stenosis undergoing carotid endarterectomy were included in the study. The patients were followed up for 10 years, and the primary endpoint was defined as a composite of adverse cardiovascular events and cardiovascular mortality, with all-cause mortality as the secondary endpoint. The baseline sST2 showed no association with carotid plaque morphology assessed using carotid duplex ultrasound (B 0.051, 95% CI −0.145–0.248, p = 0.609), nor with modified histological AHA classification based on morphological description following surgery (B −0.032, 95% CI −0.194–0.130, p = 0.698). Furthermore, sST2 was not associated with baseline clinical symptoms (B −0.105, 95% CI −0.432–0.214, p = 0.517). On the other hand, sST2 was an independent predictor for long-term adverse cardiovascular events after adjustment for age, sex, and coronary artery disease (HR 1.4, 95% CI 1.0–2.4, p = 0.048), but not for all-cause mortality (HR 1.2, 95% CI 0.8–1.7, p = 0.301). Patients with high baseline sST2 levels had a significantly higher adverse cardiovascular event rate as compared to patients with lower sST2 (log-rank p < 0.001). Although IL-33 and ST2 play a role in the pathogenesis of atherosclerosis, sST2 is not associated with carotid plaque morphology. However, sST2 is an excellent prognostic marker for long-term adverse cardiovascular outcomes in patients with high-grade carotid artery stenosis.
The Autophagy Nucleation Factor ATG9 Forms Nanoclusters with the HIV-1 Receptor DC-SIGN and Regulates Early Antiviral Autophagy in Human Dendritic Cells
Authors: Papin Laure , Lehmann Martin , Lagisquet Justine , Maarifi Ghizlane , Robert-Hebmann Véronique , Mariller Christophe , Guerardel Yann , Espert Lucile , Haucke Volker , Blanchet Fabien P.
Published: May 2023

Dendritic cells (DC) are critical cellular mediators of host immunity, notably by expressing a broad panel of pattern recognition receptors. One of those receptors, the C-type lectin receptor DC-SIGN, was previously reported as a regulator of endo/lysosomal targeting through functional connections with the autophagy pathway. Here, we confirmed that DC-SIGN internalization intersects with LC3+ autophagy structures in primary human monocyte-derived dendritic cells (MoDC). DC-SIGN engagement promoted autophagy flux which coincided with the recruitment of ATG-related factors. As such, the autophagy initiation factor ATG9 was found to be associated with DC-SIGN very early upon receptor engagement and required for an optimal DC-SIGN-mediated autophagy flux. The autophagy flux activation upon DC-SIGN engagement was recapitulated using engineered DC-SIGN-expressing epithelial cells in which ATG9 association with the receptor was also confirmed. Finally, Stimulated emission depletion (STED) microscopy performed in primary human MoDC revealed DC-SIGN-dependent submembrane nanoclusters formed with ATG9, which was required to degrade incoming viruses and further limit DC-mediated transmission of HIV-1 infection to CD4+ T lymphocytes. Our study unveils a physical association between the Pattern Recognition Receptor DC-SIGN and essential components of the autophagy pathway contributing to early endocytic events and the host’s antiviral immune response.
Novel Allosteric Effectors Targeting Human Transcription Factor TEAD
Authors: Ibrahim Mayar Tarek , Verkhivker Gennady M. , Misra Jyoti , Tao Peng
Published: May 2023

The Hippo pathway is an evolutionary conserved signaling network involved in several cellular regulatory processes. Dephosphorylation and overexpression of Yes-associated proteins (YAPs) in the Hippo-off state are common in several types of solid tumors. YAP overexpression results in its nuclear translocation and interaction with transcriptional enhanced associate domain 1-4 (TEAD1-4) transcription factors. Covalent and non-covalent inhibitors have been developed to target several interaction sites between TEAD and YAP. The most targeted and effective site for these developed inhibitors is the palmitate-binding pocket in the TEAD1-4 proteins. Screening of a DNA-encoded library against the TEAD central pocket was performed experimentally to identify six new allosteric inhibitors. Inspired by the structure of the TED-347 inhibitor, chemical modification was performed on the original inhibitors by replacing secondary methyl amide with a chloromethyl ketone moiety. Various computational tools, including molecular dynamics, free energy perturbation, and Markov state model analysis, were employed to study the effect of ligand binding on the protein conformational space. Four of the six modified ligands were associated with enhanced allosteric communication between the TEAD4 and YAP1 domains indicated by the relative free energy perturbation to original molecules. Phe229, Thr332, Ile374, and Ile395 residues were revealed to be essential for the effective binding of the inhibitors.
CRISPR-Mediated In Situ Introduction or Integration of F9-Padua in Human iPSCs for Gene Therapy of Hemophilia B
Authors: Tang Qiyu , Hu Zhiqing , Zhao Junya , Zhou Tao , Tang Shuqing , Wang Peiyun , Xiao Rou , Chen Yan , Wu Lingqian , Zhou Miaojin , Liang Desheng
Published: May 2023

Hemophilia B (HB) is an X-linked recessive disease caused by F9 gene mutation and functional coagulation factor IX (FIX) deficiency. Patients suffer from chronic arthritis and death threats owing to excessive bleeding. Compared with traditional treatments, gene therapy for HB has obvious advantages, especially when the hyperactive FIX mutant (FIX-Padua) is used. However, the mechanism by which FIX-Padua works remains ambiguous due to a lack of research models. Here, in situ introduction of F9-Padua mutation was performed in human induced pluripotent stem cells (hiPSCs) via CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs). The hyperactivity of FIX-Padua was confirmed to be 364% of the normal level in edited hiPSCs-derived hepatocytes, providing a reliable model for exploring the mechanism of the hyperactivity of FIX-Padua. Moreover, the F9 cDNA containing F9-Padua was integrated before the F9 initiation codon by CRISPR/Cas9 in iPSCs from an HB patient (HB-hiPSCs). Integrated HB-hiPSCs after off-target screening were differentiated into hepatocytes. The FIX activity in the supernatant of integrated hepatocytes showed a 4.2-fold increase and reached 63.64% of the normal level, suggesting a universal treatment for HB patients with various mutations in F9 exons. Overall, our study provides new approaches for the exploration and development of cell-based gene therapy for HB.
New Approaches in Heart Research: Prevention Instead of Cardiomyoplasty?
Authors: Gaebel Ralf , Lang Cajetan , Vasudevan Praveen , Lührs Larissa , de Carvalho Katherine Athayde Teixeira , Abdelwahid Eltyeb , David Robert
Published: May 2023

Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery disease is mainly the result of chronic disorders such as high blood pressure, diabetes, and dyslipidemia. In the modern obesogenic environment, many people are at greater risk of being overweight or obese. The hemodynamic load on the heart is influenced by extreme obesity, which often leads to myocardial infarction (MI), cardiac arrhythmias, and heart failure. In addition, obesity leads to a chronic inflammatory state and negatively affects the wound-healing process. It has been known for many years that lifestyle interventions such as exercise, healthy nutrition, and smoking cessation drastically reduce cardiovascular risk and have a preventive effect against disorders in the healing process. However, little is known about the underlying mechanisms, and there is significantly less high-quality evidence compared to pharmacological intervention studies. Due to the immense potential of prevention in heart research, the cardiologic societies are calling for research work to be intensified, from basic understanding to clinical application. The topicality and high relevance of this research area are also evident from the fact that in March 2018, a one-week conference on this topic with contributions from top international scientists took place as part of the renowned “Keystone Symposia” (“New Insights into the Biology of Exercise”). Consistent with the link between obesity, exercise, and cardiovascular disease, this review attempts to draw lessons from stem-cell transplantation and preventive exercise. The application of state-of-the-art techniques for transcriptome analysis has opened new avenues for tailoring targeted interventions to very individual risk factors.
Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspectives on Therapeutic Options and Biomarkers
Authors: Gabbia Daniela , De Martin Sara
Published: May 2023

Liver cancer remains a global health challenge and its incidence is growing worldwide [...]
Follicle-Stimulating Hormone Biological Products: Does Potency Predict Clinical Efficacy?
Authors: Lispi Monica , Humaidan Peter , Bousfield George R. , D’Hooghe Thomas , Ulloa-Aguirre Alfredo
Published: May 2023

Follicle-stimulating hormone (FSH), together with luteinizing hormone (LH) and human chorionic gonadotropin (hCG), plays a fundamental role in human reproduction. The discovery of FSH and other gonadotropins was a defining moment in our understanding of reproduction and led to the development of many treatments for infertility. In this regard, exogenous FSH has been used to treat infertility in women for decades. Today, several recombinant and highly purified urinary forms of FSH are used in medically assisted reproduction (MAR). However, differences in the macro- and micro-heterogeneity of FSH result in a variety of FSH glycoforms, with glycoform composition determining the bioactivity (or potency), pharmacokinetic/pharmacodynamic (PK/PD) profiles, and clinical efficacy of the different forms of FSH. This review illustrates how the structural heterogeneity of FSH glycoforms affects the biological activity of human FSH products, and why potency does not predict effects in humans in terms of PK, PD, and clinical response.
MicroRNA-155-5p, Reduced by Curcumin-Re-Expressed Hypermethylated BRCA1, Is a Molecular Biomarker for Cancer Risk in BRCA1-methylation Carriers
Authors: Al-Moghrabi Nisreen , Al-Showimi Maram , Al-Yousef Nujoud , AlOtai Lamya
Published: May 2023

Constitutional BRCA1-methylation is a cancer risk factor for breast (BC) and ovarian (OC) cancer. MiR-155, regulated by BRCA1, is a multifunctional microRNA that plays a crucial role in the immune system. The present study assessed the modulation of miR-155-5p expression in peripheral white blood cells (WBCs) of BC and OC patients and cancer-free (CF) BRCA1-methylation female carriers. Additionally, we investigated the potential of curcumin to suppress miR-155-5p in BRCA1-deficient breast cancer cell lines. MiR-155-5p expression was measured using a stem-loop RT-qPCR method. Gene expression levels were determined using qRT-PCR and immunoblotting. MiR-155-5p was more highly expressed in the BRCA1-hypermethylated HCC-38 and UACC-3199 BC cell lines than in the BRCA1-mutated (HCC-1937) and WT BRCA1 (MDA-MB-321) cell lines. Curcumin suppressed miR-155-5p in the HCC-38 cells but not in the HCC-1937 cells via the re-expression of BRCA1. Elevated levels of miR-155-5p were detected in patients with non-aggressive and localized breast tumors and in patients with late-stage aggressive ovarian tumors, as well as in CF BRCA1-methylation carriers. Notably, IL2RG levels were reduced in the OC and CF groups but not in the BC group. Together, our findings suggest opposing effects of WBC miR-155-5p, according to the cell and cancer type. In addition, the results point to miR-155-5p as a candidate biomarker of cancer risk among CF-BRCA1-methylation carriers.
Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review
Authors: Singh Jatinder , Goodman-Vincent Ella , Santosh Paramala
Published: May 2023

This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.
An Improved Method of Heart Rate Extraction Algorithm Based on Photoplethysmography for Sports Bracelet
Authors: Ren Binbin , Wang Zhaoyuxuan , Ma Kainan , Zhou Yiheng , Liu Ming
Published: May 2023

Heart rate measurement employing photoplethysmography (PPG) is a prevalent technique for wearable devices. However, the acquired PPG signal is often contaminated with motion artifacts, which need to be accurately removed. In cases where the PPG and accelerometer (ACC) spectra overlap at the actual heart rate, traditional discrete Fourier transform (DFT) algorithms fail to compute the heart rate accurately. This study proposed an enhanced heart rate extraction algorithm based on PPG to address the issue of PPG and ACC spectral overlap. The spectral overlap is assessed according to the morphological characteristics of both the PPG and ACC spectra. Upon detecting an overlap, the singular spectrum analysis (SSA) algorithm is employed to calculate the heart rate at the given time. The SSA algorithm effectively resolves the issue of spectral overlap by removing motion artifacts through the elimination of ACC-related time series in the PPG signal. Experimental results reveal that the accuracy of the proposed algorithm surpasses that of the traditional DFT method by 19.01%. The proposed method makes up for the deficiency posed by artifact and heart rate signal overlap in conventional algorithms and significantly improves heart rate extraction accuracy.
Electrode with a Carbon Nanotube Array for a Proton Exchange Membrane Fuel Cell
Authors: Zasypkina Adelina A. , Ivanova Nataliya A. , Spasov Dmitry D. , Mensharapov Ruslan M. , Alekseeva Olga K. , Vorobyeva Ekaterina A. , Kukueva Elena V. , Fateev Vladimir N.
Published: May 2023

One of the most important problems in the development of proton exchange membrane fuel cells remains the selection of an efficient electrocatalyst support capable of providing a low loading of active metal with minimal changes in the electrochemical surface, electronic conductivity, and activity. In this work, carbon nanotube arrays (CNTAs) grown directly on commercial gas diffusion layers (GDLs) are used to form electrodes of a new type. The CNTAs are used in the electrode as a microporous layer. The catalytic layer is formed in the microporous layer by a method that does not destroy the carbon support structure and consists of the controlled impregnation of CNTAs with the Pt-precursor with subsequent reduction in platinum particles in the surface volume of the layer. The resulting electrode was studied by scanning/transmission electron microscopy and Raman spectroscopy. This electrode provides increased electrical conductivity of the layer and can also improve stability and longer service life due to the enhanced adhesion of carbon materials to the GDL.
Life Histories and Functional Responses of Two Predatory Mites Feeding on the Stored-Grain Pest Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae)
Authors: Sun Weiwei , Xia Liyuan , Wu Yi
Published: May 2023

Cheyletus malaccensis Oudemans and Cheyletus eruditus (Schrank) are predators of stored-grain pests in China. The psocid Liposcelis bostrychophila Badonnel is prone to outbreaks in depots. To assess the potential of large-scale breeding with Acarus siro Linnaeus and the biological control potential of C. malaccensis and C. eruditus against L. bostrychophila, we determined the development times of different stages at 16, 20, 24, and 28 °C and 75% relative humidity (RH) while feeding on A. siro, as well as the functional responses of both species’ protonymphs and females to L. bostrychophila eggs at 28 °C and 75% RH. Cheyletus malaccensis had a shorter development time and longer adult survival time than C. eruditus at 28 °C and 75% RH and could establish populations faster than C. eruditus while preying on A. siro. The protonymphs of both species showed a type II functional response, while the females showed a type III functional response. Cheyletus malaccensis showed a higher predation ability than C. eruditus, and the females of both species had a higher predation ability than the protonymphs. Based on the observed development times, adult survival times, and predation efficiency, Cheyletus malaccensis has much greater biocontrol potential than C. eruditus.
Application of Machine Learning Techniques to Discern Optimal Rearing Conditions for Improved Black Soldier Fly Farming
Authors: Muinde John , Tanga Chrysantus M. , Olukuru John , Odhiambo Clifford , Tonnang Henri E. Z. , Senagi Kennedy
Published: May 2023

As the world population continues to grow, there is a need to come up with alternative sources of feed and food to combat the existing challenge of food insecurity across the globe. The use of insects, particularly the black soldier fly (BSF) Hermetia illucens (L.) (Diptera: Stratiomydiae), as a source of feed stands out due to its sustainability and reliability. Black soldier fly larvae (BSFL) have the ability to convert organic substrates to high-quality biomass rich in protein for animal feed. They can also produce biodiesel and bioplastic and have high biotechnological and medical potential. However, current BSFL production is low to meet the industry’s needs. This study used machine learning modeling approaches to discern optimal rearing conditions for improved BSF farming. The input variables studied include the cycle time in each rearing phase (i.e., the rearing period in each phase), feed formulation type, length of the beds (i.e, rearing platforms) at each phase, amount of young larvae added in the first phase, purity score (i.e, percentage of BSFL after separating from the substrate), feed depth, and the feeding rate. The output/target variable was the mass of wet larvae harvested (kg per meter) at the end of the rearing cycle. This data was trained on supervised machine learning algorithms. From the trained models, the random forest regressor presented the best root mean squared error (RMSE) of 2.91 and an R-squared value of 80.9%, implying that the model can be used to effectively monitor and predict the expected weight of BSFL to be harvested at the end of the rearing process. The results established that the top five ranked important features that inform optimal production are the length of the beds, feed formulation used, the average number of young larvae loaded in each bed, feed depth, and cycle time. Therefore, in that priority, it is expected that tuning the mentioned parameters to fall within the required levels would result in an increased mass of BSFL harvest. These data science and machine learning techniques can be adopted to understand rearing conditions and optimize the production/farming of BSF as a source of feed for animals e.g., fish, pigs, poultry, etc. A high production of these animals guarantees more food for humans, thus reducing food insecurity.
Herbicides Harm Key Orchard Predatory Mites
Authors: Bergeron Paul , Schmidt-Jeffris Rebecca
Published: May 2023

The phytoseiid mites Galendromus occidentalis and Amblydromella caudiglans are critical for conservation biological control of pest mites in Washington State, U.S.A. apples. While the non-target effects of insecticides on phytoseiids are well described, research on herbicide effects is limited. Using laboratory bioassays, we examined lethal (female mortality) and sublethal (fecundity, egg hatch, larval survival) effects of seven herbicides and five adjuvants on A. caudiglans and G. occidentalis. The effects of mixing herbicides with recommended adjuvants were also tested to determine if the addition of an adjuvant increased herbicide toxicity. Glufosinate was the least selective herbicide tested, causing 100% mortality in both species. Paraquat caused 100% mortality in A. caudiglans and 56% mortality in G. occidentalis. Sublethal effects were significant for both species when exposed to oxyfluorfen. Adjuvants did not cause non-target effects in A. caudiglans. The non-ionic surfactant and methylated seed oil increased mortality and decreased reproduction in G. occidentalis. The high toxicity of glufosinate and paraquat for both predators is concerning; these are the primary “burn down” herbicide alternatives to glyphosate, which is decreasing in use due to consumer toxicity concerns. Field studies are needed to determine the extent to which herbicides disrupt orchard biological control, focusing on glufosinate, paraquat, and oxyfluorfen. Consumer preferences will need to be balanced with natural enemy conservation.
Quantification of Indocyanine Green Fluorescence Imaging in General, Visceral and Transplant Surgery
Authors: Pollmann Lukas , Juratli Mazen , Roushansarai Nicola , Pascher Andreas , Hölzen Jens Peter
Published: May 2023

Near-infrared (NIR) imaging with indocyanine green (ICG) has proven to be useful in general, visceral, and transplant surgery. However, most studies have performed only qualitative assessments. Therefore, a systematic overview of all studies performing quantitative indocyanine green evaluation in general, visceral, and transplant surgeries should be conducted. Free term and medical subject heading (MeSH) term searches were performed in the Medline and Cochrane databases until October 2022. The main categories of ICG quantification were esophageal surgery (24.6%), reconstructive surgery (24.6%), and colorectal surgery (21.3%). Concordantly, anastomotic leak (41%) was the main endpoint, followed by the assessment of flap perfusion (23%) and the identification of structures and organs (14.8%). Most studies examined open surgery (67.6%) or laparoscopic surgery (23.1%). The analysis was mainly carried out using manufacturer software (44.3%) and open-source software (15.6%). The most frequently analyzed parameter was intensity over time for blood flow assessment, followed by intensity alone or intensity-to-background ratios for structure and organ identification. Intraoperative ICG quantification could become more important with the increasing impact of robotic surgery and machine learning algorithms for image and video analysis.
Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis
Authors: Zi Liuliu , Ma Wangbin , Zhang Lilong , Qiao Boyang , Qiu Zhendong , Xu Junhui , Zhang Jiacheng , Ye Yahong , Yang Yueyuan , Dong Keshuai , Chen Chen , Wang Weixing , Zhao Qingyan
Published: May 2023

Uridine is a key metabolite used as a substrate for the production of DNA, RNA, and glucose, and it is mainly synthesized in the liver. Currently, it is not known whether uridine levels are altered in the tumor microenvironment of patients with hepatocellular carcinoma (HCC) and whether uridine can be a target for tumor therapy. In this study, the detection of genes associated with de novo uridine synthesis, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) (n = 115), and dihydroorotate dehydrogenase (DHODH) (n = 115) in HCC tissues through tissue microarrays revealed that the expression of CAD and DHODH was higher in tumor compared with paraneoplastic tissues. Next, we collected tumor tissues from surgically resected HCC patients and the corresponding adjacent non-tumor tissues (n = 46) for LC–MS/MS assays. The results showed that the median and interquartile ranges of uridine content in non-tumor and tumor tissues were 640.36 (504.45–807.43) and 484.22 (311.91–626.73) nmol/g, respectively. These results suggest that uridine metabolism is disturbed in HCC patients. To further investigate whether uridine can be used as a tumor-therapeutic target, a series of high concentrations of uridine were incubated with HCC cells in vitro and in vivo. It was observed that uridine dose-dependently inhibited the proliferation, invasion, and migration of HCC cells by activating the ferroptosis pathway. Overall, these results reveal for the first time the range of uridine content in human HCC tissues and suggest that uridine may be a new target for HCC therapy.
Depression in Children and Adolescents with Chronic Kidney Disease—Review of Available Literature
Authors: Dryjańska Natalia , Kiliś-Pstrusińska Katarzyna
Published: May 2023

Depression is a significant health problem gaining increasing relevance, especially among children and adolescents. It is known that the incidence of depression is higher in patients suffering from chronic diseases, such as chronic kidney disease (CKD). This review aims to discuss the prevalence of depression in children and adolescents with CKD and its impact on the quality of life of these patients (HRQoL). The research was conducted using online databases with keywords: depression in children and adolescents, depression and chronic diseases, chronic kidney disease, and health-related quality of life. It was found that the risk for developing depression is higher for adolescents and females, and with the use of negative coping strategies, lack of caregiver nurturance, and poor socioeconomic status. In patients with pediatric CKD, the stage of the disease, age of CKD diagnosis, and type of treatment were found to significantly impact HRQoL and contribute to caregiver burden. Depression was more commonly found in children suffering from CKD. It causes significant mental distress to the child and contributes to the caregiver’s burden. Screening for depression among CKD patients is advised. In depressed patients, transdiagnostic tools should be used to alleviate some of the symptoms. In children at risk of developing depression, preventative strategies should be considered.
Monitored Anesthesia Care Using Remimazolam and Ketamine Combination for Brief Gynecological Surgeries: A Report for Four Cases
Authors: Choi Soron , Lee Ganghyun , Jung Jiwook , Lee Taeyoung , Park Sangyoong
Published: May 2023

Remimazolam is a benzodiazepine with rapid onset and recovery time. Ketamine provides analgesia and sedation without compromising hemodynamics. Combining both agents may provide good anesthesia and analgesia with fewer complications. We report four cases of monitored anesthesia care with a combination of remimazolam and ketamine for brief gynecological surgeries. We applied 0.5 mg/kg bolus ketamine and infused patients with remimazolam at 6 mg/kg/h for induction and 1 mg/kg/h for maintenance. Then, 25 µg of fentanyl was administered for analgesia 4 min before the procedure, and additional fentanyl was administered as needed. Remimazolam was discontinued shortly after surgery. We conducted satisfactory monitored anesthesia care with a combination of remimazolam and ketamine in all four cases.