bluuebunny/crossref_metadata_2025 huggingface dataset:
Foliar Silicon Spray before Summer Cutting Propagation Enhances Resistance to Powdery Mildew of Daughter Plants
Authors: Xiao Jie , Li Yali , Jeong Byoung Ryong
Published: March 2022

Silicon (Si) has beneficial effects on not only plant growth but also against biotic and abiotic stresses. However, a few studies focus on how Si application helps strawberry (Fragaria × ananassa Duch.) resist powdery mildew. The aim of this work was to find out the optimal Si application method before cutting propagation to enhance the resistance to powdery mildew in strawberry “daughter” plants. Naturally infected “mother” plants of ‘Sulhyang’, ‘Maehyang’, and ‘Kuemsil’ strawberries were supplied with Si. Potassium silicate (K2SiO3) at a final concentration of 75 mg·L−1 Si was either added to the medium for drenching or sprayed to the leaves of the “mother” or “daughter” plant, or soluble Si fertilizer was used to dress the “mother” plant. The Si application significantly increased the shoot fresh weight of the “daughter” plants. Supplemental Si also increased the contents of phosphorus (P), potassium (K), and magnesium (Mg). In addition, the Si treatment decreased the damage of powdery mildew by increased level of proline content and suppressive reactive oxygen species. After applying Si, the length and density of hyphae on the leaf surface decreased. In addition, the infected area of “daughter” plant leaves covered with powdery mildew decreased. This study also demonstrated that Si increased the expression of resistance-gene and decreased the expression of susceptibility-gene of strawberry. Overall, Si application promoted the growth of the “daughter” plants regardless of the application method. Direct foliar Si spray to the “daughter” plants before cutting propagation is recommended to increase their resistance to powdery mildew.
Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches
Authors: Lim Gyutae , You Ka Young , Lee Jeong Hyun , Jeon Moon Kook , Lee Byung Ho , Ryu Jae Yong , Oh Kwang-Seok
Published: March 2022

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists.
Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19
Authors: Mahdi Mohamed , Hermán Levente , Réthelyi János M. , Bálint Bálint László
Published: March 2022

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.
Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir
Authors: Gringmuth Marieke , Walther Jenny , Greiser Sebastian , Toussaint Magali , Schwalm Benjamin , Kool Marcel , Kortmann Rolf-Dieter , Glasow Annegret , Patties Ina
Published: March 2022

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic.
Recent and Ongoing Research into Metastatic Osteosarcoma Treatments
Authors: Harris Michael A. , Hawkins Christine J.
Published: March 2022

The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed.
Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution
Authors: de Pinho Pessoa Flávia Melo Cunha , Machado Caio Bezerra , da Silva Emerson Lucena , da Costa Pantoja Laudreísa , Ribeiro Rodrigo Monteiro , de Moraes Maria Elisabete Amaral , de Moraes Filho Manoel Odorico , Montenegro Raquel Carvalho , Khayat André Salim , Moreira-Nunes Caroline Aquino
Published: March 2022

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.
Bioactive Oxadiazoles 2.0
Authors: Palumbo Piccionello Antonio
Published: April 2022

Oxadiazoles are electron-poor, five-membered aromatic heterocycles that contain one oxygen and two nitrogen atoms [...]
Katanin-Dependent Microtubule Ordering in Association with ABA Is Important for Root Hydrotropism
Authors: Miao Rui , Siao Wei , Zhang Na , Lei Zuliang , Lin Deshu , Bhalerao Rishikesh P. , Lu Congming , Xu Weifeng
Published: April 2022

Root hydrotropism refers to root directional growth toward soil moisture. Cortical microtubule arrays are essential for determining the growth axis of the elongating cells in plants. However, the role of microtubule reorganization in root hydrotropism remains elusive. Here, we demonstrate that the well-ordered microtubule arrays and the microtubule-severing protein KATANIN (KTN) play important roles in regulating root hydrotropism in Arabidopsis. We found that the root hydrotropic bending of the ktn1 mutant was severely attenuated but not root gravitropism. After hydrostimulation, cortical microtubule arrays in cells of the elongation zone of wild-type (WT) Col-0 roots were reoriented from transverse into an oblique array along the axis of cell elongation, whereas the microtubule arrays in the ktn1 mutant remained in disorder. Moreover, we revealed that abscisic acid (ABA) signaling enhanced the root hydrotropism of WT and partially rescued the oryzalin (a microtubule destabilizer) alterative root hydrotropism of WT but not ktn1 mutants. These results suggest that katanin-dependent microtubule ordering is required for root hydrotropism, which might work downstream of ABA signaling pathways for plant roots to search for water.
Hippo Signaling in the Endometrium
Authors: Moon Sohyeon , Hwang Semi , Kim Byeongseok , Lee Siyoung , Kim Hyoukjung , Lee Giwan , Hong Kwonho , Song Hyuk , Choi Youngsok
Published: April 2022

The uterus is essential for embryo implantation and fetal development. During the estrous cycle, the uterine endometrium undergoes dramatic remodeling to prepare for pregnancy. Angiogenesis is an essential biological process in endometrial remodeling. Steroid hormones regulate the series of events that occur during such remodeling. Researchers have investigated the potential factors, including angiofactors, involved in endometrial remodeling. The Hippo signaling pathway discovered in the 21st century, plays important roles in various cellular functions, including cell proliferation and cell death. However, its role in the endometrium remains unclear. In this review, we describe the female reproductive system and its association with the Hippo signaling pathway, as well as novel Hippo pathway genes and potential target genes.
Impact of Vitamin D in Prophylaxis and Treatment in Tuberculosis Patients
Authors: Papagni Roberta , Pellegrino Carmen , Di Gennaro Francesco , Patti Giulia , Ricciardi Aurelia , Novara Roberta , Cotugno Sergio , Musso Maria , Guido Giacomo , Ronga Luigi , Stolfa Stefania , Bavaro Davide Fiore , Romanelli Federica , Totaro Valentina , Lattanzio Rossana , De Iaco Giuseppina , Palmieri Fabrizio , Saracino Annalisa , Gualano Gina
Published: April 2022

Vitamin D plays a crucial role in many infectious diseases, such as tuberculosis (TB), that remains one of the world’s top infectious killers with 1.5 million deaths from TB in 2021. Vitamin D suppresses the replication of Mycobacterium tuberculosis in vitro and showed a promising role in TB management as a result of its connection with oxidative balance. Our review encourages the possible in vivo benefit of a joint administration with other vitamins, such as vitamin A, which share a known antimycobacterial action with vitamin D. However, considering the low incidence of side effects even at high dosages and its low cost, it would be advisable to assess vitamin D level both in patients with active TB and high-risk groups and administer it, at least to reach sufficiency levels.
Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways
Authors: Kato Masaki , Ogata Haruhiko , Tahara Hidetoshi , Shimamoto Akira , Takekita Yoshiteru , Koshikawa Yosuke , Nishida Keiichiro , Nonen Shinpei , Higasa Koichiro , Kinoshita Toshihiko
Published: April 2022

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-β, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.
Optogenetic Control of PIP2 Interactions Shaping ENaC Activity
Authors: Abd El-Aziz Tarek Mohamed , Kaur Amanpreet , Shapiro Mark S. , Stockand James D. , Archer Crystal R.
Published: April 2022

The activity of the epithelial Na+ Channel (ENaC) is strongly dependent on the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 binds two distinct cationic clusters within the N termini of β- and γ-ENaC subunits (βN1 and γN2). The affinities of these sites were previously determined using short synthetic peptides, yet their role in sensitizing ENaC to changes in PIP2 levels in the cellular system is not well established. We addressed this question by comparing the effects of PIP2 depletion and recovery on ENaC channel activity and intracellular Na+ levels [Na+]i. We tested effects on ENaC activity with mutations to the PIP2 binding sites using the optogenetic system CIBN/CRY2-OCRL to selectively deplete PIP2. We monitored changes of [Na+]i by measuring the fluorescent Na+ indicator, CoroNa Green AM, and changes in channel activity by performing patch clamp electrophysiology. Whole cell patch clamp measurements showed a complete lack of response to PIP2 depletion and recovery in ENaC with mutations to βN1 or γN2 or both sites, compared to wild type ENaC. Whereas mutant βN1 also had no change in CoroNa Green fluorescence in response to PIP2 depletion, γN2 did have reduced [Na+]i, which was explained by having shorter CoroNa Green uptake and half-life. These results suggest that CoroNa Green measurements should be interpreted with caution. Importantly, the electrophysiology results show that the βN1 and γN2 sites on ENaC are each necessary to permit maximal ENaC activity in the presence of PIP2.
Viral Hepatitis, Cholesterol Metabolism, and Cholesterol-Lowering Natural Compounds
Authors: Liou Je-Wen , Mani Hemalatha , Yen Jui-Hung
Published: April 2022

Hepatitis is defined as inflammation of the liver; it can be acute or chronic. In chronic cases, the prolonged inflammation gradually damages the liver, resulting in liver fibrosis, cirrhosis, and sometimes liver failure or cancer. Hepatitis is often caused by viral infections. The most common causes of viral hepatitis are the five hepatitis viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While HAV and HEV rarely (or do not) cause chronic hepatitis, a considerable proportion of acute hepatitis cases caused by HBV (sometimes co-infected with HDV) and HCV infections become chronic. Thus, many medical researchers have focused on the treatment of HBV and HCV. It has been documented that host lipid metabolism, particularly cholesterol metabolism, is required for the hepatitis viral infection and life cycle. Thus, manipulating host cholesterol metabolism-related genes and proteins is a strategy used in fighting the viral infections. Efforts have been made to evaluate the efficacy of cholesterol-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the treatment of hepatitis viral infections; promising results have been obtained. This review provides information on the relationships between hepatitis viruses and host cholesterol metabolism/homeostasis, as well as the discovery/development of cholesterol-lowering natural phytochemicals that could potentially be applied in the treatment of viral hepatitis.
Essential Protective Role of Catalytically Active Antibodies (Abzymes) with Redox Antioxidant Functions in Animals and Humans
Authors: Tolmacheva Anna S. , Nevinsky Georgy A.
Published: April 2022

During the life of aerobic organisms, the oxygen resulting from numerous reactions is converted into reactive oxygen species (ROS). Many ROS are dangerous due to their high reactivity; they are strong oxidants, and react with various cell components, leading to their damage. To protect against ROS overproduction, enzymatic and non-enzymatic systems are evolved in aerobic cells. Several known non-enzymatic antioxidants have a relatively low specific antioxidant activity. Superoxide dismutases, catalase, glutathione peroxidase, glutathione S-transferase, thioredoxin, and the peroxiredoxin families are the most important enzyme antioxidants. Artificial antibodies catalyzing redox reactions using different approaches have been created. During the past several decades, it has been shown that the blood and various biological fluids of humans and animals contain natural antibodies that catalyze different redox reactions, such as classical enzymes. This review, for the first time, summarizes data on existing non-enzymatic antioxidants, canonical enzymes, and artificial or natural antibodies (abzymes) with redox functions. Comparing abzymes with superoxide dismutase, catalase, peroxide-dependent peroxidase, and H2O2-independent oxidoreductase activities with the same activities as classical enzymes was carried out. The features of abzymes with the redox activities are described, including their exceptional diversity in the optimal pH values, dependency and independence on various metal ions, and the reaction rate constants for healthy donors and patients with different autoimmune diseases. The entire body of evidence indicates that abzymes with redox antioxidant activities existing in the blood for a long time compared to enzymes are an essential part of the protection system of humans and animals from oxidative stress.
Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein
Authors: Ledoux Julie , Stolyarchuk Maxim , Bachelier Enki , Trouvé Alain , Tchertanov Luba
Published: April 2022

Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1’s oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments.
GABAA Receptor-Stabilizing Protein Ubqln1 Affects Hyperexcitability and Epileptogenesis after Traumatic Brain Injury and in a Model of In Vitro Epilepsy in Mice
Authors: Kürten Tabea , Ihbe Natascha , Ueberbach Timo , Distler Ute , Sielaff Malte , Tenzer Stefan , Mittmann Thomas
Published: April 2022

Posttraumatic epilepsy (PTE) is a major public health concern and strongly contributes to human epilepsy cases worldwide. However, an effective treatment and prevention remains a matter of intense research. The present study provides new insights into the gamma aminobutyric acid A (GABAA)-stabilizing protein ubiquilin-1 (ubqln1) and its regulation in mouse models of traumatic brain injury (TBI) and in vitro epilepsy. We performed label-free quantification on isolated cortical GABAergic interneurons from GAD67-GFP mice that received unilateral TBI and discovered reduced expression of ubqln1 24 h post-TBI. To investigate the link between this regulation and the development of epileptiform activity, we further studied ubqln1 expression in hippocampal and cortical slices. Epileptiform events were evoked pharmacologically in acute brain slices by administration of picrotoxin (PTX, 50 μM) and kainic acid (KA, 500 nM) and recorded in the hippocampal CA1 subfield using Multi-electrode Arrays (MEA). Interestingly, quantitative Western blots revealed significant decreases in ubqln1 expression 1–7 h after seizure induction that could be restored by application of the non-selective monoamine oxidase inhibitor nialamide (NM, 10 μM). In picrotoxin-dependent dose–response relationships, NM administration alleviated the frequency and peak amplitude of seizure-like events (SLEs). These findings indicate a role of the monoamine transmitter systems and ubqln1 for cortical network activity during posttraumatic epileptogenesis.
Do Synovial Inflammation and Meniscal Degeneration Impact Clinical Outcomes of Patients Undergoing Arthroscopic Partial Meniscectomy? A Histological Study
Authors: Olivotto Eleonora , Belluzzi Elisa , Pozzuoli Assunta , Cigolotti Augusto , Scioni Manuela , Goldring Steven R. , Goldring Mary B. , Ruggieri Pietro , Ramonda Roberta , Grigolo Brunella , Trisolino Giovanni , Favero Marta
Published: April 2022

The menisci exert a prominent role in joint stabilization and in the distribution of mechanical loading. Meniscal damage is associated with increased risk of knee OA. The aim of this study was to characterize the synovial membrane and meniscal tissues in patients undergoing arthroscopic partial meniscectomy for meniscal tear and to evaluate association with clinical outcomes. A total of 109 patients were recruited. Demographic and clinical data were collected. Visual Analogic Scale (VAS) measuring pain and Knee injury and Osteoarthritis Outcome Score (KOOS) were recorded at baseline and at 2-years follow-up. Histological and immunohistochemical characterizations were performed on synovial membranes and meniscal tissues. More than half of the patients demonstrated synovial mononuclear cell infiltration and hyperplasia. Synovial fibrosis was present in most of the patients; marked vascularity and CD68 positivity were observed. Inflammation had an impact on both pain and knee symptoms. Patients with synovial inflammation had higher values of pre-operative VAS and inflammation. Higher pre-operative pain was observed in patients with meniscal MMP-13 production. In conclusion, multivariate analysis showed that synovial inflammation was associated with pre-operative total KOOS scores, knee symptoms, and pain. Moreover, meniscal MMP-13 expression was found to be associated with pre-operative pain in multivariate analysis. Thus, targeting inflammation of the synovial membrane and meniscus might reduce clinical symptoms and dysfunction at the time of surgery.
Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies
Authors: Nash Benjamin M. , Ma Alan , Ho Gladys , Farnsworth Elizabeth , Minoche Andre E. , Cowley Mark J. , Barnett Christopher , Smith Janine M. , Loi To Ha , Wong Karen , St Heaps Luke , Wright Dale , Dinger Marcel E. , Bennetts Bruce , Grigg John R. , Jamieson Robyn V.
Published: April 2022

The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or underinvestigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs.
Design and Nonadiabatic Photoisomerization Dynamics Study of a Three-Stroke Light-Driven Molecular Rotary Motor
Authors: Ma Jianzheng , Yang Sujie , Zhao Di , Jiang Chenwei , Lan Zhenggang , Li Fuli
Published: April 2022

Working cycle of conventional light-driven molecular rotary motors (LDMRMs), especially Feringa-type motors, usually have four steps, two photoisomerization steps, and two thermal helix inversion (THI) steps. THI steps hinder the ability of the motor to operate at lower temperatures and limit the rotation speed of LDMRMs. A three-stroke LDMRM, 2-(2,7-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-1,2-dihydro-3H-pyrrol-3-one (DDIY), is proposed, which is capable of completing an unidirectional rotation by two photoisomerization steps and one thermal helix inversion step at room temperature. On the basis of trajectory surface-hopping simulation at the semi-empirical OM2/MRCI level, the EP→ZP and ZP→EM nonadiabatic photoisomerization dynamics of DDIY were systematically analyzed. Quantum yields of EP→ZP and ZP→EM photoisomerization of DDIY are ca. 34% and 18%, respectively. Both EP→ZP and ZP→EM photoisomerization processes occur on an ultrafast time scale (ca. 100–300 fs). This three-stroke LDMRM may stimulate further research for the development of new families of more efficient LDMRMs.
Rosmarinic Acid, as an NHE1 Activator, Decreases Skin Surface pH and Improves the Skin Barrier Function
Authors: Jung Seung-Won , Park Gi Hyun , Kim Eunjung , Yoo Kang Min , Kim Hea Won , Lee Jin Soo , Chang Min Youl , Shin Kyong-Oh , Park Kyungho , Choi Eung Ho
Published: April 2022

Stratum corneum (SC) pH regulates skin barrier functions and elevated SC pH is an important factor in various inflammatory skin diseases. Acidic topical formulas have emerged as treatments for impaired skin barriers. Sodium proton exchanger 1 (NHE1) is an important factor in SC acidification. We investigated whether topical applications containing an NHE1 activator could improve skin barrier functions. We screened plant extracts to identify NHE1 activators in vitro and found Melissa officinalis leaf extract. Rosmarinic acid, a component of Melissa officinalis leaf extract, significantly increased NHE1 mRNA expression levels and NHE1 production. Immunofluorescence staining of NHE1 in 3D-cultured skin revealed greater upregulation of NHE1 expression by NHE1 activator cream, compared to vehicle cream. Epidermal lipid analysis revealed that the ceramide level was significantly higher upon application of the NHE1 activator cream on 3D-cultured skin, compared to application of a vehicle cream. In a clinical study of 50–60-year-old adult females (n = 21), application of the NHE1 activator-containing cream significantly improved skin barrier functions by reducing skin surface pH and transepidermal water loss and increasing skin hydration, compared to patients who applied vehicle cream and those receiving no treatment. Thus, creams containing NHE1 activators, such as rosmarinic acid, could help maintain or recover skin barrier functions.
Scanning Technologies to Building Information Modelling: A Review
Authors: Rashdi Rabia , Martínez-Sánchez Joaquín , Arias Pedro , Qiu Zhouyan
Published: March 2022

Building information modelling (BIM) is evolving significantly in the architecture, engineering and construction industries. BIM involves various remote-sensing tools, procedures and standards that are useful for collating the semantic information required to produce 3D models. This is thanks to LiDAR technology, which has become one of the key elements in BIM, useful to capture a semantically rich geometric representation of 3D models in terms of 3D point clouds. This review paper explains the ‘Scan to BIM’ methodology in detail. The paper starts by summarising the 3D point clouds of LiDAR and photogrammetry. LiDAR systems based on different platforms, such as mobile, terrestrial, spaceborne and airborne, are outlined and compared. In addition, the importance of integrating multisource data is briefly discussed. Various methodologies involved in point-cloud processing such as sampling, registration and semantic segmentation are explained in detail. Furthermore, different open BIM standards are summarised and compared. Finally, current limitations and future directions are highlighted to provide useful solutions for efficient BIM models.
Potential Distribution of Wild Host Plants of the Boll Weevil (Anthonomus grandis) in the United States and Mexico
Authors: Sánchez-Reyes Uriel Jeshua , Jones Robert W. , Raszick Tyler J. , Ruiz-Arce Raul , Sword Gregory A.
Published: March 2022

The boll weevil (Anthonomus grandis Boheman) reproduces on a reported 13 species of wild host plants in North America, two in the United States and 12 in Mexico. The distributions of these plants are of economic importance to pest management and provide insight into the evolutionary history and origin of the BW. However, detailed information regarding the distributions of many of these species is lacking. In this article, we present distribution models for all of the reported significant BW host plants from Mexico and the United States using spatial distribution modelling software. Host plant distributions were divided into two groups: “eastern” and “western.” In Mexico, Hampea nutricia along the Gulf Coast was the most important of the eastern group, and the wild cottons, Gossypium aridum and Gossypium thurberi were most important in the western group. Other species of Hampea, Gossypium, and Cienfuegosia rosei have relatively restricted distributions and are of apparent minimal economic importance. Cienfuegosia drummondii is the only truly wild host in the southern United States, east of New Mexico. Factors determining potential distributions were variable and indicated that species were present in five vegetation types. Ecological and economic considerations of host plant distributions are discussed, as well as threats to host plant conservation.
C/EBPα Regulates PxTreh1 and PxTreh2 Trehalase-Related Bt Resistance in Plutella xylostella (L.)
Authors: Liu Jia , Liu Zheming , Ma Haihao , Yu Yaying , Zhang Chengjia , Zheng Wei , Man Yilong , Zhu Hang , Zhou Yong , Chen Xi , Zhou Xiaomao , Zeng Aiping
Published: March 2022

Trehalase regulates energy metabolism in insects by converting trehalose into two glucose molecules. High amounts of trehalase are critical for insect flight and larval stress resistance. However, whether trehalase participates in the development of pesticide resistance remains unclear. In this study, we explored this phenomenon and the mechanism that underlies the regulation of Trehalase transcription. We found that overexpression of PxTreh1 and PxTreh2 induced Bacillus thuringiensis (Bt) resistance in Plutella xylostella. The promoter sequences of PxTreh1 and PxTreh2 were also cloned and identified. The dual-luciferase reporter system and RNA interference technology revealed that the expression of PxTreh1 and PxTreh2 genes is possibly regulated by the CCAAT enhancer-binding protein (C/EBPα). A yeast one-hybrid experiment confirmed the interaction between C/EBPα and the PxTreh2 promoter. The findings of this study suggest that C/EBPα mediates the adaptability of P. xylostella to adverse environmental stressors by regulating the expression of trehalase.
Toxicity and Control Efficacy of an Organosilicone to the Two-Spotted Spider Mite Tetranychus urticae and Its Crop Hosts
Authors: Chen Jin-Cui , Ma Zhong-Zheng , Gong Ya-Jun , Cao Li-Jun , Wang Jia-Xu , Guo Shao-Kun , Hoffmann Ary A. , Wei Shu-Jun
Published: March 2022

Organosilicone molecules represent important components of surfactants added to pesticides to improve pest control efficiency, but these molecules also have pesticidal properties in their own right. Here, we examined toxicity and control efficacy of Silwet 408, a trisiloxane ethoxylate-based surfactant, to the two-spotted spider mite (TSSM), Tetranychus urticae and its crop hosts. Silwet 408 was toxic to nymphs and adults of TSSM but did not affect eggs. Field trials showed that the control efficacy of 1000 mg/L Silwet 408 aqueous solution reached 96% one day after spraying but declined to 54% 14 days after spraying, comparable to 100 mg/L cyetpyrafen, a novel acaricide. A second spraying of 1000 mg/L Silwet 408 maintained control efficacy at 97% when measured 14 days after spraying. However, Silwet 408 was phytotoxic to eggplant, kidney bean, cucumber, and strawberry plants, although phytotoxicity to strawberry plants was relatively low and declined further seven days after application. Our study showed that while the organosilicone surfactant Silwet 408 could be used to control the TSSM, its phytotoxicity to crops should be considered.
Genome-Wide Association of New-Onset Hypertension According to Renin Concentration: The Korean Genome and Epidemiology Cohort Study
Authors: Lee Sung-Bum , Park Byoungjin , Hong Kyung-Won , Jung Dong-Hyuk
Published: March 2022

The renin-angiotensin system (RAS) is a crucial regulator of vascular resistance and blood volume in the body. This study aimed to examine the genetic predisposition of the plasma renin concentration influencing future hypertension incidence. Based on the Korean Genome and Epidemiology Cohort dataset, 5211 normotensive individuals at enrollment were observed over 12 years, categorized into the low-renin and high-renin groups. We conducted genome-wide association studies for the total, low-renin, and high-renin groups. Among the significant SNPs, the lead SNPs of each locus were focused on for further interpretation. The effect of genotypes was determined by logistic regression analysis between controls and new-onset hypertension, after adjusting for potential confounding variables. During a mean follow-up period of 7.6 years, 1704 participants (32.7%) developed hypertension. The low-renin group showed more incidence rates of new-onset hypertension (35.3%) than the high-renin group (26.5%). Among 153 SNPs in renin-related gene regions, two SNPs (rs11726091 and rs8137145) showed an association in the high-renin group, four SNPs (rs17038966, rs145286444, rs2118663, and rs12336898) in the low-renin group, and three SNPs (rs1938859, rs7968218, and rs117246401) in the total population. Most significantly, the low-renin SNP rs12336898 in the SPTAN1 gene, closely related to vascular wall remodeling, was associated with the development of hypertension (p-value = 1.3 × 10−6). We found the candidate genetic polymorphisms according to blood renin concentration. Our results might be a valuable indicator for hypertension risk prediction and preventive measure, considering renin concentration with genetic susceptibility.
Effects of COPD on Left Ventricular and Left Atrial Deformation in Patients with Acute Myocardial Infarction: Strain Analysis Using Speckle-Tracking Echocardiography
Authors: Grebe Julian , Müller Tobias , Altiok Ertunc , Becker Michael , Keszei András P. , Marx Nikolaus , Dreher Michael , Daher Ayham
Published: March 2022

Myocardial strain analysis, which describes myocardial deformation (shortening or lengthening), provides more detailed information about left ventricular (LV) and atrial (LA) functions than conventional echocardiography and delivers prognostic information. To analyze the effects of COPD on left heart function upon acute myocardial infarction (AMI), consecutive AMI patients were retrospectively screened, and patients were included if a post-AMI echocardiography and results of recent pulmonary function tests (PFTs) were available. Strain analysis was performed by a cardiologist who was blinded to clinical information. Overall, 109 AMI patients were included (STEMI: 38%, non-STEMI: 62%). COPD patients (41%) had significantly more impaired LV “global-longitudinal-strain” (LV-GLS) compared to non-COPD patients (−15 ± 4% vs. −18 ± 4%; p < 0.001, respectively), even after adjusting for LV-ejection-fraction (LVEF) and age (mean estimated difference: 1.7%, p = 0.009). Furthermore, COPD patients had more impaired LA strain (LAS) than non-COPD patients in all cardiac cycle phases (estimated mean differences after adjusting for LVEF and age: during reservoir phase: −7.5% (p < 0.001); conduit phase: 5.5% (p < 0.001); contraction phase: 1.9% (p = 0.034)). There were no correlations between PFT variables and strain values. In conclusion, the presence of COPD was associated with more impaired LV and LA functions after AMI, as detected by strain analysis, which was independent of age, LVEF, and PFT variables.
Is Prostate Urethral Lift Effective in Patients with Multiple Comorbidities?
Authors: Ahn Sun-Tae , Lee Dong-Hyun , Cho Sun-Bum , Lee Hyun-Soo , Han Da-Eun , Park Tae-Yong , Moon Du-Geon
Published: March 2022

A prostatic urethral lift (PUL) can be performed under local anesthesia in patients normally at high risk for general anesthesia due to multiple comorbidities. However, the clinical efficacy of PULs in patients with multiple comorbidities remains unknown. Therefore, in this this study, we aimed to evaluate the clinical efficacy of the PUL in patients with a high number of comorbidities by comparing its clinical efficacy in these patients with that in healthy individuals. We performed a retrospective observational cohort study, in which patients who underwent a PUL between December 2016 and January 2019 at a single tertiary care center were categorized into two groups: healthy individuals who wanted to preserve sexual function (Group 1) and patients with a high number of comorbidities who were at high risk for general anesthesia, based on an American Society of Anesthesiologists (ASA) score of ≥3 (Group 2). The International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), and post-void residual urine (PVR) were obtained preoperatively and compared throughout the 2-year follow-up. A total of 66 patients were enrolled, of whom 36 patients were included in Group 1 and 30 in Group 2. In Group 1, IPSS, IPSS quality of life (QoL), and Qmax significantly improved and were then maintained during follow-up, whereas, in Group 2, improvements in these parameters were not maintained during follow-up, except for IPSS QoL. Eleven patients (36%) in Group 2 required additional treatment for the recurrence of lower urinary tract symptoms. In conclusion, patients with a high number of comorbidities had a low therapeutic effect after PUL, suggesting a high rate of treatment failure. Therefore, comorbidity status should be considered when evaluating the potential benefits of the PUL procedure during preoperative counseling.
Randomized Controlled Trial Comparing a Multidisciplinary Intervention by a Geriatrician and a Cardiologist to Usual Care after a Heart Failure Hospitalization in Older Patients: The SENECOR Study
Authors: Herrero-Torrus Marta , Badosa Neus , Roqueta Cristina , Ruiz-Bustillo Sonia , Solé-González Eduard , Belarte-Tornero Laia C. , Valdivielso-Moré Sandra , Vázquez Olga , Farré Núria
Published: March 2022

Background: The prognosis of older patients after a heart failure (HF) hospitalization is poor. Methods: In this randomized trial, we consecutively assigned 150 patients 75 years old or older with a recent heart failure hospitalization to follow-up by a cardiologist (control) or follow-up by a cardiologist and a geriatrician (intervention). The primary outcome was all-cause hospitalization at a one-year follow-up. Results: All-cause hospitalization occurred in 47 of 75 patients (62.7%) in the intervention group and in 58 of 75 patients (77.3%) in the control group (hazard ratio, 0.67; 95% confidence interval, 0.46 to 0.99; p = 0.046). The number of patients with at least one HF hospitalization was similar in both groups (34.7% in the intervention group vs. 40% in the control group, p = 0.5). There were a total of 236 hospitalizations during the study period. The main reasons for hospitalization were heart failure (38.1%) and infection (14.8%). Mortality was 24.7%. Heart failure was the leading cause of mortality (54.1% of all deaths), without differences between groups. Conclusions: A follow-up by a cardiologist and geriatrician in older patients after an HF hospitalization was superior to a cardiologist’s follow-up in reducing all-cause hospitalization in older patients. (Funded by Beca Primitivo de la Vega, Fundación MAPFRE. ClinicalTrials.gov number, NCT03555318).
Inconsistencies and Ambiguities in Liver-Disease-Related Contraindications—A Systematic Analysis of SmPCs/PI of Major Drug Markets
Authors: Weisbach Laura , Schuster Anna K. , Hartmann Michael , Fromm Martin F. , Maas Renke , Farker Katrin
Published: March 2022

Liver disease is a common condition worldwide that can cause alterations in drug disposition and susceptibility to drug toxicities, with increased risk of adverse drug reactions. European Summaries of Product Characteristics (SmPCs) and United States Prescribing Information (US PI) should therefore be comprehensible to prescribers regarding their liver-associated contraindications to ensure safe prescribing. This study aimed to evaluate the ambiguity of terminology used in communicating liver-associated absolute contraindications in SmPCs/PI of commonly prescribed drugs in four major drug markets (Germany, Switzerland, the United Kingdom, and the United States) by assigning wordings to different categories and analyzing their clinical comprehensibility. For US PI, 79% did not contain liver-related contraindications, compared to 2, 13, and 6% of German, Swiss, and British SmPCs, respectively. Study findings indicate that out of 228 examined SmPCs/PI containing liver-related contraindications, 77, 79, 76, and 52% contained unclear wording in the German, Swiss, British, and American drug market, respectively. Only 40% (German), 52% (Swiss), 39% (British), and 29% (American) of SmPCs/PI included terms with explicit wording. Including more precise statements in SmPCs/PI based on laboratory parameters (such as albumin) or scores (e.g., the Child–Pugh score) to objectify the severity of liver disease may improve the clarity of SmPCs/PI and the safety of drug prescription.