bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Systolic Blood Pressure and Diabetic Retinopathy in Both Hypertensive and Normotensive Patients with Type 2 Diabetes: Risk Factors and Healthcare Implications
Authors: Li Yu-Ting , Wang Yi , Hu Xiu-Jing , Chen Jia-Heng , Li Yun-Yi , Zhong Qi-Ya , Cheng Hui , Mohammed Bedru , Liang Xiao-Ling , Hernandez Jose , Huang Wen-Yong , Wang Harry
Published: May 2021

A common diabetes-related microvascular complication is diabetic retinopathy (DR), yet associations between blood pressure (BP) and risks for DR in diabetic patients with normal BP received inadequate attention. This may lead to ‘clinical inertia’ in early DR prevention. We aimed to assess whether the extent to which systolic BP levels were associated with DR in patients with type 2 diabetes (T2DM) and normal BP were similar to that in those with concurrent hypertension. Data were collected from patients with T2DM attending ophthalmic check-up with primary care referral (n = 2510). BP measurements, clinical laboratory tests, and dilated fundus examination were conducted according to gold standard of diagnosis and routine clinical procedure. Of all subjects, over 40% were normotensive and one fifth were clinically diagnosed with DR. Systolic BP levels increased across DR categories of escalated severity irrespective of the coexistence of hypertension. Ordinal logistic regression analysis showed that an increased systolic BP was independently and significantly associated with DR (adjusted odds ratio [aOR] = 1.020, p < 0.001 for hypertensives; aOR = 1.019, p = 0.018 for normotensives), after adjusting for diabetes duration, sex, lifestyles, and haemoglobin A1c levels. Regular monitoring of systolic BP should not be neglected in routine diabetes management even when BP falls within the normal range. (200 words)
Estimation of Benchmark Dose of Cumulative Cadmium Exposure for Renal Tubular Effect
Authors: Nogawa Kazuhiro , Suwazono Yasushi , Watanabe Yuuka , Elinder Carl-Gustaf
Published: May 2021

Objectives: The aim of this study was to determine the no observed adverse effect level (NOAEL), the lowest observed adverse effect level (LOAEL) and the benchmark dose low (BMDL) of cadmium exposure by re-evaluation of the dose–response relationship between cumulative cadmium exposure and renal tubular damage reported previously. Methods: The participants were workers (326 men and 114 women) employed for at least three months between 1931 and 1982. Blood cadmium (Cd-B) and air cadmium (Cd-A) were collected at regular intervals with urinary β2-microglobulin as the tubular effect marker. Cumulative Cd-A and Cd-B were estimated by multiplying concentration and working period. The BMDL was calculated using Benchmark Dose Software (version 3.1.2). The benchmark response (BMR) was set at 5% or 10%. Results: By logistic regression, the NOAEL of mean cumulative Cd-B was 7122 months nmol/L. The LOAEL of cumulative Cd-A and least-squares cumulative Cd-B was 691 yrs μg/m3 and 8586 months nmol/L, respectively. Among various models for dose–response relationships, a probit model was adopted as the best fitting model. The obtained BMDLs of cumulative Cd-A were 272.3 yrs µg/m3 (BMR5%) and 707.5 yrs µg/m3 (BMR10%). The BMDLs of mean cumulative Cd-B were 3967.2 months nmol/L (BMR5%) and 7798.1 months nmol/L (BMR10%). The BMDLs of least-squares cumulative Cd-B were 3588.6 months nmol/L (BMR5%) and 8616.3 months nmol/L (BMR10%). Assuming a working period of 40 years, the BMDLs for BMR10% corresponded to 17.7 µg/m3 (Cd-A) and 1.8~2.0 µg/L (Cd-B). Discussion: This study provides new valuable information to enhance the reliability of limit values and thereby make a significant contribution to preventing the health effects of Cd in exposed workers.
A Prepubertal Mice Model to Study the Growth Pattern of Early Ovarian Follicles
Authors: Chen Yingjun , Liu Qinghua , Liu Ruiyan , Yang Chan , Wang Xiaodong , Ran Zaohong , Zhou Shanshan , Li Xiang , He Changjiu
Published: May 2021

Early folliculogenesis begins with the activation of the follicle and ends with the formation of the follicular antrum, which takes up most of the time of folliculogenesis. In this long process, follicles complete a series of developmental events, including but not limited to granulosa cell (GC) proliferation, theca folliculi formation, and antrum formation. However, the logical or temporal sequence of these events is not entirely clear. This study demonstrated in a mouse model that completion of early folliculogenesis required a minimum of two weeks. The oocyte reached its largest size in the Type 4–5 stage, which was therefore considered as the optimum period for studying oogenesis. Postnatal days (PD) 10–12 were regarded as the crucial stage of theca folliculi formation, as Lhcgr sharply increased during this stage. PD13–15 was the rapid growth period of early follicles, which was characterized by rapid cell proliferation, the sudden emergence of the antrum, and increased Fshr expression. The ovarian morphology remained stable during PD15–21, but antrum follicles accumulated gradually. Atresia occurred at all stages, with the lowest rate in Type 3 follicles and no differences among early Type 4–6 follicles. The earliest vaginal opening was observed at PD24, almost immediately after the first growing follicular wave. Therefore, the period of PD22–23 could be considered as a suitable period for studying puberty initiation. This study objectively revealed the pattern of early folliculogenesis and provided time windows for the study of biological events in this process.
When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood
Authors: Stokum Jesse A. , Cannarsa Gregory J. , Wessell Aaron P. , Shea Phelan , Wenger Nicole , Simard J. Marc
Published: May 2021

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain.
Plant Copper Amine Oxidases: Key Players in Hormone Signaling Leading to Stress-Induced Phenotypic Plasticity
Authors: Fraudentali Ilaria , Rodrigues-Pousada Renato A. , Angelini Riccardo , Ghuge Sandip A. , Cona Alessandra
Published: May 2021

Polyamines are ubiquitous, low-molecular-weight aliphatic compounds, present in living organisms and essential for cell growth and differentiation. Copper amine oxidases (CuAOs) oxidize polyamines to aminoaldehydes releasing ammonium and hydrogen peroxide, which participates in the complex network of reactive oxygen species acting as signaling molecules involved in responses to biotic and abiotic stresses. CuAOs have been identified and characterized in different plant species, but the most extensive study on a CuAO gene family has been carried out in Arabidopsis thaliana. Growing attention has been devoted in the last years to the investigation of the CuAO expression pattern during development and in response to an array of stress and stress-related hormones, events in which recent studies have highlighted CuAOs to play a key role by modulation of a multilevel phenotypic plasticity expression. In this review, the attention will be focused on the involvement of different AtCuAOs in the IAA/JA/ABA signal transduction pathways which mediate stress-induced phenotypic plasticity events.
ELTD1—An Emerging Silent Actor in Cancer Drama Play
Authors: Sevastre Ani-Simona , Buzatu Iuliana M. , Baloi Carina , Oprita Alexandru , Dragoi Alexandra , Tataranu Ligia G. , Alexandru Oana , Tudorache Stefania , Dricu Anica
Published: May 2021

The epidermal growth factor, latrophilin, and seven transmembrane domain–containing protein 1 (ELTD1), is a member of the G–protein coupled receptors (GPCRs) superfamily. Although discovered in 2001, ELTD1 has been investigated only by a few research groups, and important data about its role in normal and tumor cells is still missing. Even though its functions and structure are not yet fully understood, recent studies show that ELTD1 has a role in both physiological and pathological angiogenesis, and it appears to be a very important biomarker and a molecular target in cancer diseases. Upregulation of ELTD1 in malignant cells has been reported, and correlated with poor cancer prognosis. This review article aims to compile the existing data and to discuss the current knowledge on ELTD1 structure and signaling, and its role in physiological and neoplastic conditions.
A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder
Authors: Ghafouri-Fard Soudeh , Badrlou Elham , Taheri Mohammad , Dürsteler Kenneth M. , Beatrix Brühl Annette , Sadeghi-Bahmani Dena , Brand Serge
Published: May 2021

Aim: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). Methods: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. Results: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. Conclusion: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients.
Next Generation Cereal Crop Yield Enhancement: From Knowledge of Inflorescence Development to Practical Engineering by Genome Editing
Authors: Liu Lei , Lindsay Penelope L. , Jackson David
Published: May 2021

Artificial domestication and improvement of the majority of crops began approximately 10,000 years ago, in different parts of the world, to achieve high productivity, good quality, and widespread adaptability. It was initiated from a phenotype-based selection by local farmers and developed to current biotechnology-based breeding to feed over 7 billion people. For most cereal crops, yield relates to grain production, which could be enhanced by increasing grain number and weight. Grain number is typically determined during inflorescence development. Many mutants and genes for inflorescence development have already been characterized in cereal crops. Therefore, optimization of such genes could fine-tune yield-related traits, such as grain number. With the rapidly advancing genome-editing technologies and understanding of yield-related traits, knowledge-driven breeding by design is becoming a reality. This review introduces knowledge about inflorescence yield-related traits in cereal crops, focusing on rice, maize, and wheat. Next, emerging genome-editing technologies and recent studies that apply this technology to engineer crop yield improvement by targeting inflorescence development are reviewed. These approaches promise to usher in a new era of breeding practice.
Characterization of Glutathione Peroxidase 4 in Rat Oocytes, Preimplantation Embryos, and Selected Maternal Tissues during Early Development and Implantation
Authors: Kreheľová Andrea , Kovaříková Veronika , Domoráková Iveta , Solár Peter , Pastornická Alena , Pavliuk-Karachevtseva Andriana , Rybárová Silvia , Hodorová Ingrid , Mihalik Jozef
Published: May 2021

This study aimed to describe glutathione peroxidase 4 (GPx4) in rat oocytes, preimplantation embryos, and female genital organs. After copulation, Sprague Dawley female rats were euthanized with anesthetic on the first (D1), third (D3), and fifth days of pregnancy (D5). Ovaries, oviducts, and uterine horns were removed, and oocytes and preimplantation embryos were obtained. Immunohistochemical, immunofluorescent, and Western blot methods were employed. Using immunofluorescence, we detected GPx4 in both the oocytes and preimplantation embryos. Whereas in the oocytes, GPx4 was homogeneously diffused, in the blastomeres, granules were formed, and in the blastocysts, even clusters were present mainly around the cell nuclei. Employing immunohistochemistry, we detected GPx4 inside the ovary in the corpus luteum, stroma, follicles, and blood vessels. In the oviduct, the enzyme was present in the epithelium, stroma, blood vessels, and smooth muscles. In the uterus, GPx4 was found in the endometrium, myometrium, blood vessels, and stroma. Moreover, we observed GPx4 positive granules in the uterine gland epithelium on D1 and D3 and cytoplasm of fibroblasts forming in the decidua on D5. Western blot showed the highest GPx4 levels in the uterus and the lowest levels in the ovary. Our results show that the GPx4 is necessary as early as in the preimplantation development of a new individual because we detected it in an unfertilized oocyte in a blastocyst and not only after implantation, as was previously thought.
Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision
Authors: Lee Wen-Ling , Liu Chia-Hao , Cheng Min , Chang Wen-Hsun , Liu Wei-Min , Wang Peng-Hui
Published: May 2021

Intrauterine adhesion (IUA), and its severe form Asherman syndrome (Asherman’s syndrome), is a mysterious disease, often accompanied with severe clinical problems contributing to a significant impairment of reproductive function, such as menstrual disturbance (amenorrhea), infertility or recurrent pregnancy loss. Among these, its correlated infertility may be one of the most challenging problems. Although there are many etiologies for the development of IUA, uterine instrumentation is the main cause of IUA. Additionally, more complicated intrauterine surgeries can be performed by advanced technology, further increasing the risk of IUA. Strategies attempting to minimize the risk and reducing its severity are urgently needed. The current review will expand the level of our knowledge required to face the troublesome disease of IUA. It is separated into six sections, addressing the introduction of the normal cyclic endometrial repairing process and its abruption causing the formation of IUA; the etiology and prevalence of IUA; the diagnosis of IUA; the classification of IUA; the pathophysiology of IUA; and the primary prevention of IUA, including (1) delicate surgical techniques, such as the use of surgical instruments, energy systems, and pre-hysteroscopic management, (2) barrier methods, such as gels, intrauterine devices, intrauterine balloons, as well as membrane structures containing hyaluronate–carboxymethylcellulose or polyethylene oxide–sodium carboxymethylcellulose as anti-adhesive barrier.
Speckle-Tracking Echocardiography with Novel Imaging Technique of Higher Frame Rate
Authors: Fujikura Kana , Makkiya Mohammed , Farooq Muhammad , Xing Yun , Humphrey Wayne , Mustehsan Mohammad Hashim , Garcia Mario J. , Taub Cynthia C.
Published: May 2021

Background: The accuracy of speckle-tracking echocardiography (STE) depends on temporal resolution. The goal of this study was to demonstrate the feasibility of relatively high frame rate (rHi-FR) (~200 fps) for STE. Methods: In this prospective study, echocardiographic images were acquired using clinical scanners on patients with normal left ventricular systolic function using rHi-FR and conventional frame rate (Reg-FR) (~50 FPS). GLS values were evaluated on apical 4-, 2- and 3-chamber images acquired in both rHi-FR and Reg-FR. Inter-observer and intra-observer variabilities were assessed in rHi-FR and Reg-FR. Results: There were 143 echocardiograms evaluated in this study. The frame rate of rHi-FR was 190 ± 25 and Reg-FR was 50 ± 3, and the heart rate was 71 ± 13. Absolute strain values measured in rHi-FR were significantly higher than those measured in Reg-FR (all p < 0.001). Inter-observer and intra-observer correlations were strong in both rHi-FR and Reg-FR. Conclusions: We demonstrated that absolute strain values were significantly higher using rHi-FR when compared with Reg-FR. It is plausible that higher temporal resolution enabled the measurement of myocardial strain at desired time point. Further investigations are necessary to evaluate the value of rHi-FR to assess myocardial strain in the setting of tachycardia.
A Systematic Review and Meta-Analysis of the Implementation of High-Performance Cardiopulmonary Resuscitation on Out-of-Hospital Cardiac Arrest Outcomes
Authors: Ng Qin Xiang , Han Ming Xuan , Lim Yu Liang , Arulanandam Shalini
Published: May 2021

Despite numerous technological and medical advances, out-of-hospital cardiac arrests (OHCAs) still suffer from suboptimal survival rates and poor subsequent neurological and functional outcomes amongst survivors. Multiple studies have investigated the implementation of high-quality prehospital resuscitative efforts, and across these studies, different terms describing high-quality resuscitative efforts have been used, such as high-performance CPR (HP CPR), multi-tiered response (MTR) and minimally interrupted cardiac resuscitation (MICR). There is no universal definition for HP CPR, and dissimilar designs have been employed. This systematic review thus aimed to review current evidence on HP CPR implementation and examine the factors that may influence OHCA outcomes. Eight studies were systematically reviewed, and seven were included in the final meta-analysis. Random-effects meta-analysis found a significantly improved likelihood of prehospital return of spontaneous circulation (pooled odds ratio (OR) = 1.46, 95% CI: 1.16 to 1.82, p < 0.001), survival-to-discharge (pooled OR = 1.32, 95% CI: 1.16 to 1.50, p < 0.001) and favourable neurological outcomes (pooled OR = 1.24, 95% CI: 1.11 to 1.39, p < 0.001) with HP CPR or similar interventions. However, the studies had generally high heterogeneity (I2 greater than 50%) and overall moderate-to-severe risk for bias. Moving forward, a randomised, controlled trial is necessary to shed light on the subject.
Genetic Variants of Alcohol Metabolizing Enzymes and Alcohol-Related Liver Cirrhosis Risk
Authors: Ayuso Pedro , García-Martín Elena , Cornejo-García José A. , Agúndez José A. G. , Ladero José María
Published: May 2021

Alcohol-related liver disease (ARLD) is a major public health issue caused by excessive alcohol consumption. ARLD encompasses a wide range of chronic liver lesions, alcohol-related liver cirrhosis being the most severe and harmful state. Variations in the genes encoding the enzymes, which play an active role in ethanol metabolism, might influence alcohol exposure and hence be considered as risk factors of developing cirrhosis. We conducted a case-control study in which 164 alcohol-related liver cirrhosis patients and 272 healthy controls were genotyped for the following functional single nucleotide variations (SNVs): ADH1B gene, rs1229984, rs1041969, rs6413413, and rs2066702; ADH1C gene, rs35385902, rs283413, rs34195308, rs1693482, and rs35719513; CYP2E1 gene, rs3813867. Furthermore, copy number variations (CNVs) for ADH1A, ADH1B, ADH1C, and CYP2E1 genes were analyzed. A significant protective association with the risk of developing alcohol-related liver cirrhosis was observed between the mutant alleles of SNVs ADH1B rs1229984 (Pc value = 0.037) and ADH1C rs283413 (Pc value = 0.037). We identified CNVs in all genes studied, ADH1A gene deletions being more common in alcohol-related liver cirrhosis patients than in control subjects, although the association lost statistical significance after multivariate analyses. Our findings support that susceptibility to alcohol-related liver cirrhosis is related to variations in alcohol metabolism genes.
Future Perspectives of Proton Therapy in Minimizing the Toxicity of Breast Cancer Radiotherapy
Authors: Musielak Marika , Suchorska Wiktoria M. , Fundowicz Magdalena , Milecki Piotr , Malicki Julian
Published: May 2021

The toxicity of radiotherapy is a key issue when analyzing the eligibility criteria for patients with breast cancer. In order to obtain better results, proton therapy is proposed because of the more favorable distribution of the dose in the patient’s body compared with photon radiotherapy. Scientific groups have conducted extensive research into the improved efficacy and lower toxicity of proton therapy for breast cancer. Unfortunately, there is no complete insight into the potential reasons and prospects for avoiding undesirable results. Cardiotoxicity is considered challenging; however, researchers have not presented any realistic prospects for preventing them. We compared the clinical evidence collected over the last 20 years, providing the rationale for the consideration of proton therapy as an effective solution to reduce cardiotoxicity. We analyzed the parameters of the dose distribution (mean dose, Dmax, V5, and V20) in organs at risk, such as the heart, blood vessels, and lungs, using the following two irradiation techniques: whole breast irradiation and accelerated partial breast irradiation. Moreover, we presented the possible causes of side effects, taking into account biological and technical issues. Finally, we collected potential improvements in higher quality predictions of toxic cardiac effects, like biomarkers, and model-based approaches to give the full background of this complex issue.
Patient-Centered Care for People with Depression and Anxiety: An Integrative Review Protocol
Authors: Pinho Lara Guedes de , Correia Tânia , Lopes Manuel José , Fonseca César , Marques Maria do Céu , Sampaio Francisco , do Arco Helena Reis
Published: May 2021

Introduction: Depression and anxiety are mental diseases found worldwide, with the tendency to worsen in the current pandemic period. These illnesses contribute the most to the world’s rate of years lived with disability. We aim to identify and synthesize indicators for the care process of the person with depression and/or anxiety disorders, based on patient-centered care, going through the stages of diagnostic assessment, care planning, and intervention. Methods and analysis: An integrative literature review will be conducted, and the research carried out on the following databases: MEDLINE, PsycINFO, Scopus, and Psychology and Behavioral Sciences Collection, CINAHL, Web of Science, TrialRegistry, and MedicLatina. The research strategy contains the following terms MesH or similar: “patient-centered care,” “depression,” and “anxiety.” Two independent revisers will perform the inclusion and exclusion criteria analysis, the quality analysis of the data, and its extraction for synthesis. Disagreements will be resolved by a third revisor. All studies related to diagnostic assessment, care planning, or intervention strategies will be included as long as they focus on care focused on people with depression and anxiety, regardless of the context. Given the plurality of the eligible studies, we used the narrative synthesis method for the analysis of the diagnostic assessment, the care and intervention planning, and the facilitators and barriers. PROSPERO registration number: CRD42021235405.
Driving Factor Analysis of Ecosystem Service Balance for Watershed Management in the Lancang River Valley, Southwest China
Authors: Liu Shiliang , Sun Yongxiu , Wu Xue , Li Weiqiang , Liu Yixuan , Tran Lam-Son Phan
Published: May 2021

Revealing the spatio-temporal change of the supply, demand and balance of ecosystem services (ESs) associated with human activities and land-use changes is of great significance for watershed ecosystem management. Taking the Lancang river valley as a case, we explicitly studied the ES spatial characteristics, using the land use/land cover (LULC) matrix model, Optimized Hot Spot Analysis and landscape pattern analysis. Furthermore, we screened out the dominant explanatory variables that had significant influence on the ES supply, demand and balance by means of the Geographical Weighted Regression (GWR) method at pixel scale. The results showed that the ES demand intensity varied little throughout the watershed, while the downstream ES supply capacity and balance values were greater than upstream ones. Meanwhile, the hotspots of ES supply and demand were mainly distributed in the south part with coldspots in the north part. Human activity factors integrating landscape pattern variables were verified to have a negative impact on the ES balance in general. Among them, the Largest Patch Index (LPI) had a negative influence on the majority of pixels, while the Gross Domestic Product (GDP), cultivated land ratio and Area Weighted Average Patch Fractal Dimension (AWAPFD) had positive effects on a few pixels. This study will provide scientific support for regional ecosystem service trade-off and regulation at multiple scales.
Ticks, Hair Loss, and Non-Clinging Babies: A Novel Tick-Based Hypothesis for the Evolutionary Divergence of Humans and Chimpanzees
Authors: Brown Jeffrey G.
Published: May 2021

Human straight-legged bipedalism represents one of the earliest events in the evolutionary split between humans (Homo spp.) and chimpanzees (Pan spp.), although its selective basis is a mystery. A carrying-related hypothesis has recently been proposed in which hair loss within the hominin lineage resulted in the inability of babies to cling to their mothers, requiring mothers to walk upright to carry their babies. However, a question remains for this model: what drove the hair loss that resulted in upright walking? Observers since Darwin have suggested that hair loss in humans may represent an evolutionary strategy for defence against ticks. The aim of this review is to propose and evaluate a novel tick-based evolutionary hypothesis wherein forest fragmentation in hominin paleoenvironments created conditions that were favourable for tick proliferation, selecting for hair loss in hominins and grooming behaviour in chimpanzees as divergent anti-tick strategies. It is argued that these divergent anti-tick strategies resulted in different methods for carrying babies, driving the locomotor divergence of humans and chimpanzees.
Exploratory Study of the Association between the Severity of Idiopathic Intracranial Hypertension and Electroretinogram Photopic Negative Response Amplitude Obtained Using a Handheld Device
Authors: Raharja Antony , Leo Shaun M. , Chow Isabelle , Indusegaran Mathura , Hammond Christopher J. , Mahroo Omar A. , Wong Sui H.
Published: May 2021

The photopic negative response (PhNR) is a negative component of the photopic flash electroretinogram that follows the b-wave and is thought to arise from the retinal ganglion cells. Reduction in its amplitude in idiopathic intracranial hypertension (IIH) has been previously documented using formal electroretinography. This study explored the use of a handheld device (RETeval, LKC technologies, Gaithersburg, MD, USA) in 72 IIH patients of varying stages and severity (and seven controls) and investigated associations between PhNR parameters and disease severity. PhNR amplitudes at 72 ms (P72) and p-ratio (ratio to b-wave peak value) differed significantly across groups, with a trend towards smaller amplitudes in those with severe IIH, defined as papilloedema with Modified Frisén Scale (MFS) ≥ 3, retinal nerve fibre layer (RNFL) ≥ 150 μm or atrophic papilloedema (p = 0.0048 and p = 0.018 for P72 and p-ratio, respectively). PhNR parameters did not correlate with MFS, RNFL thickness, standard automated perimetry mean deviation or macular ganglion cell layer volume. This study suggests that PhNR measurement using a handheld device is feasible and could potentially augment the assessment of disease severity in IIH. The clinical utility of PhNR monitoring in IIH patients requires further investigation.
Purcell’s Three-Link Swimmer: Assessment of Geometry and Gaits for Optimal Displacement and Efficiency
Authors: Nuevo-Gallardo Cristina , Traver José Emilio , Tejado Inés , Vinagre Blas M.
Published: May 2021

This paper studies the displacement and efficiency of a Purcell’s three-link microswimmer in low Reynolds number regime, capable of moving by the implementation of a motion primitive or gait. An optimization is accomplished attending to the geometry of the swimmer and the motion primitives, considering the shape of the gait and its amplitude. The objective is to find the geometry of the swimmer, amplitude and shape of the gaits which make optimal the displacement and efficiency, in both an individual way and combined (the last case will be referred to as multiobjective optimization). Three traditional gaits are compared with two primitives proposed by the authors and other three gaits recently defined in the literature. Results demonstrate that the highest displacement is obtained by the Tam and Hosoi optimal velocity gait, which also achieves the best efficiency in terms of energy consumption. The rectilinear and Tam and Hosoi optimal efficiency gaits are the second optimum primitives. Regarding the multiobjective optimization and considering the two criteria with the same weight, the optimum gaits turn out to be the rectilinear and Tam and Hosoi optimal efficiency gaits. Thus, the conclusions of this study can help designers to select, on the one hand, the best swimmer geometry for a desired motion primitive and, on the other, the optimal method of motion for trajectory tracking for such a kind of Purcell’s swimmers depending on the desired control objective.
Energy-Efficient Production Planning Using a Two-Stage Fuzzy Approach
Authors: Wu Hsin-Chieh , Tsai Horng-Ren , Chen Tin-Chih Toly , Hsu Keng-Wei
Published: May 2021

Analyzing energy consumption is an important task for a factory. In order to accomplish this task, most studies fit the relationship between energy consumption and product design features, process characteristics, or equipment types. However, the energy-saving effects of product yield learning are rarely considered. To bridge this gap, this study proposes a two-stage fuzzy approach to estimate the energy savings brought about by yield improvement. In the two-stage fuzzy approach, a fuzzy polynomial programming approach is first utilized to fit the yield-learning process of a product. Then, the relationship between monthly electricity consumption and increase in yield was fit to estimate the energy savings brought about by the improvement in yield. The actual case of a dynamic random-access memory factory was used to illustrate the applicability of the two-stage fuzzy approach. According to the experiment results, product yield learning can greatly reduce electricity consumption.
International Trade and Human Capital Investment with Heterogeneous Firms and Workers: Modeling and Analysis
Authors: Jung Jaewon
Published: May 2021

Though the importance of organizational behavior and human decision processes within firms for the firm performance has largely been recognized in the business and management literature, much less attention has been devoted to studying such implications in the international trade context. This paper develops a general-equilibrium trade model in which heterogeneous workers make an investment decision in acquiring advanced managerial skills and choose their optimal effort level based on their comparative advantage. In doing so, we show how globalization-induced human capital accumulation within firms leads to sustainable economic growth. We also show that workers’ organizational belief and CEO’s managerial vision may be an important element for the human capital formation within firms and for the performance of firms in a global economy.
Marine Anthraquinones: Pharmacological and Toxicological Issues
Authors: Greco Giulia , Turrini Eleonora , Catanzaro Elena , Fimognari Carmela
Published: May 2021

The marine ecosystem, populated by a myriad of animals, plants, and microorganisms, is an inexhaustible reservoir of pharmacologically active molecules. Among the multiple secondary metabolites produced by marine sources, there are anthraquinones and their derivatives. Besides being mainly known to be produced by terrestrial species, even marine organisms and the uncountable kingdom of marine microorganisms biosynthesize anthraquinones. Anthraquinones possess many different biological activities, including a remarkable antitumor activity. However, due to their peculiar chemical structures, anthraquinones are often associated with toxicological issues, even relevant, such as genotoxicity and mutagenicity. The aim of this review is to critically describe the anticancer potential of anthraquinones derived from marine sources and their genotoxic and mutagenic potential. Marine-derived anthraquinones show a promising anticancer potential, although clinical studies are missing. Additionally, an in-depth investigation of their toxicological profile is needed before advocating anthraquinones as a therapeutic armamentarium in the oncological area.
Second Primary Tumors in Patients with Gastrointestinal Stromal Tumors: A Single-Center Experience
Authors: Koçer Murat , Muallaoğlu Sadık , Çetin Bülent , Coşkun Hasan Şenol , Karahan Nermin , Gürdal Osman
Published: May 2021

Background and Objectives: In this study, we investigated the frequency and type of second primary malignant tumors (SPMTs) accompanying gastrointestinal stromal tumors (GISTs), patient and tumor characteristics, and follow-up and survival data. Materials and Methods: We included 20 patients with SPMTs from a total of 103 patients with GISTs in a single center in Turkey. At the time of GIST diagnosis, patient age, sex, presentation symptoms, localization, pathological features of the tumor, stage, recurrence risk scoring for localized disease, treatments received, time of SPMT association, follow-up times, and survival analysis were recorded for each patient. Localization, histopathology, and stage of SPMT accompanying GISTs were also recorded accordingly. Results: SPMT was detected in 19.4% of patients with GISTs. Of the patients, 50% were men and 50% were women. The mean age at the time of diagnosis of GIST was 63.8 ± 10.81 years (range: 39–77 years). Of the GISTs, 60% were localized in the stomach, 25% in the small intestine, and 70% were at low risk. Of the SPMTs, 60% were in the gastrointestinal system. SPMTs were diagnosed as synchronous with GISTs in 50% of the patients. The mean follow-up period of the patients from the diagnosis of GIST was 45.6 (0.43–129.6) months. When the data were finalized, 5% died due to GIST, 35% died due to SPMT, and 15% died due to non-disease-related causes. Conclusions: SPMT was detected in 19.4% of patients with GISTs. GISTs were frequently located in the stomach, and most of them were at low risk. The most common SPMTs were gastrointestinal system tumors, and their coexistence was found to be synchronous. Most patients died due to SPMT during follow-up.
Preparation and Characterization of a Sol–Gel AHEC Pore-Sealing Film Prepared on Micro Arc Oxidized AZ31 Magnesium Alloy
Authors: Zhang Longlong , Wu Yuanzhi , Zeng Tian , Wei Yu , Zhang Guorui , Liang Jun , Cao Baocheng
Published: May 2021

The purpose of this study was to improve the cellular compatibility and corrosion resistance of AZ31 magnesium alloy and to prepare a biodegradable medical material. An aminated hydroxyethyl cellulose (AHEC) coating was successfully prepared on the surface of a micro-arc oxide +AZ31 magnesium alloy by sol–gel spinning. The pores of the micro-arc oxide coating were sealed. A polarization potential test analysis showed that compared to the single micro-arc oxidation coating, the coating after sealing with AHEC significantly improved the corrosion resistance of the AZ31 magnesium alloy and reduced its degradation rate in simulated body fluid (SBF). The CCK-8 method and cell morphology experiments showed that the AHEC + MAO coating prepared on the AZ31 magnesium alloy had good cytocompatibility and bioactivity.
Functional Interrelationships of Microorganisms in Iron-Based Anaerobic Wastewater Treatment
Authors: Ahmed Musfique , Anwar Rifat , Deng Dongyang , Garner Emily , Lin Lian-Shin
Published: May 2021

This study explicated the functional activities of microorganisms and their interrelationships under four previously reported iron reducing conditions to identify critical factors that governed the performance of these novel iron-dosed anaerobic biological wastewater treatment processes. Various iron-reducing bacteria (FeRB) and sulfate reducing bacteria (SRB) were identified as the predominant species that concurrently facilitated organics oxidation and the main contributors to removal of organics. The high organic contents of wastewater provided sufficient electron donors for active growth of both FeRB and SRB. In addition to the organic content, Fe (III) and sulfate concentrations (expressed by Fe/S ratio) were found to play a significant role in regulating the microbial abundance and functional activities. Various fermentative bacteria contributed to this FeRB-SRB synergy by fermenting larger organic compounds to smaller compounds, which were subsequently used by FeRB and SRB. Feammox (ferric reduction coupled to ammonium oxidation) bacterium was identified in the bioreactor fed with wastewater containing ammonium. Organic substrate level was a critical factor that regulated the competitive relationship between heterotrophic FeRB and Feammox bacteria. There were evidences that suggested a synergistic relationship between FeRB and nitrogen-fixing bacteria (NFB), where ferric iron and organics concentrations both promoted microbial activities of FeRB and NFB. A concept model was developed to illustrate the identified functional interrelationships and their governing factors for further development of the iron-based wastewater treatment systems.
CesL Regulates Type III Secretion Substrate Specificity of the Enteropathogenic E. coli Injectisome
Authors: Díaz-Guerrero Miguel , Gaytán Meztlli O. , Soto Eduardo , Espinosa Norma , García-Gómez Elizabeth , Marcos-Vilchis Arely , Andrade Angel , González-Pedrajo Bertha
Published: May 2021

The type III secretion system (T3SS) is a complex molecular device used by several pathogenic bacteria to translocate effector proteins directly into eukaryotic host cells. One remarkable feature of the T3SS is its ability to secrete different categories of proteins in a hierarchical manner, to ensure proper assembly and timely delivery of effectors into target cells. In enteropathogenic Escherichia coli, the substrate specificity switch from translocator to effector secretion is regulated by a gatekeeper complex composed of SepL, SepD, and CesL proteins. Here, we report a characterization of the CesL protein using biochemical and genetic approaches. We investigated discrepancies in the phenotype among different cesL deletion mutants and showed that CesL is indeed essential for translocator secretion and to prevent premature effector secretion. We also demonstrated that CesL engages in pairwise interactions with both SepL and SepD. Furthermore, while association of SepL to the membrane does not depended on CesL, the absence of any of the proteins forming the heterotrimeric complex compromised the intracellular stability of each component. In addition, we found that CesL interacts with the cytoplasmic domains of the export gate components EscU and EscV. We propose a mechanism for substrate secretion regulation governed by the SepL/SepD/CesL complex.
An Integrated Approach toward NanoBRET Tracers for Analysis of GPCR Ligand Engagement
Authors: Killoran Michael P. , Levin Sergiy , Boursier Michelle E. , Zimmerman Kristopher , Hurst Robin , Hall Mary P. , Machleidt Thomas , Kirkland Thomas A. , Friedman Ohana Rachel
Published: May 2021

Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.
Application of Optimal Control Theory to Fourier Transform Ion Cyclotron Resonance
Authors: Martikyan Vardan , Beluffi Camille , Glaser Steffen J. , Delsuc Marc-André , Sugny Dominique
Published: May 2021

We study the application of Optimal Control Theory to Ion Cyclotron Resonance. We test the validity and the efficiency of this approach for the robust excitation of an ensemble of ions with a wide range of cyclotron frequencies. Optimal analytical solutions are derived in the case without any pulse constraint. A gradient-based numerical optimization algorithm is proposed to take into account limitation in the control intensity. The efficiency of optimal pulses is investigated as a function of control time, maximum amplitude and range of excited frequencies. A comparison with adiabatic and SWIFT pulses is done. On the basis of recent results in Nuclear Magnetic Resonance, this study highlights the potential usefulness of optimal control in Ion Cyclotron Resonance.
Screening and Comparison of Lignin Degradation Microbial Consortia from Wooden Antiques
Authors: Zhang Wen , Ren Xueyan , Lei Qiong , Wang Lei
Published: May 2021

Lignin, which is a component of wood, is difficult to degrade in nature. However, serious decay caused by microbial consortia can happen to wooden antiques during the preservation process. This study successfully screened four microbial consortia with lignin degradation capabilities (J-1, J-6, J-8 and J-15) from decayed wooden antiques. Their compositions were identified by genomic sequencing, while the degradation products were analyzed by GC-MS. The lignin degradation efficiency of J-6 reached 54% after 48 h with an initial lignin concentration of 0.5 g/L at pH 4 and rotation speed of 200 rpm. The fungal consortium of J-6 contained Saccharomycetales (98.92%) and Ascomycota (0.56%), which accounted for 31% of the total biomass. The main bacteria in J-6 were Shinella sp. (47.38%), Cupriavidus sp. (29.84%), and Bosea sp. (7.96%). The strongest degradation performance of J-6 corresponded to its composition, where Saccharomycetales likely adapted to the system and improved lignin degradation enzymes activities, and the abundant bacterial consortium accelerated lignin decomposition. Our work demonstrated the potential utilization of microbial consortia via the synergy of microbial consortia, which may overcome the shortcomings of traditional lignin biodegradation when using a single strain, and the potential use of J-6 for lignin degradation/removal applications.
Novel D-A-D Fluorescent Dyes Based on 9-(p-Tolyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazole as a Donor Unit for Solution-Processed Organic Light-Emitting-Diodes
Authors: Korshunov Vladislav M. , Mikhailov Maxim S. , Chmovzh Timofey N. , Vashchenko Andrey A. , Gudim Nikita S. , Mikhalchenko Lyudmila V. , Taydakov Ilya V. , Rakitin Oleg A.
Published: May 2021

New fluorescent D-A-D dyes containing 9-(p-tolyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazole as a donor unit and 2,1,3-benzochalcogenadiazoles as an electron-withdrawing group were synthesized. The photoluminescent and electroluminescent properties of novel dyes for fluorescent OLED application were investigated. It was demonstrated that the replacement of lightweight heteroatoms by heavier ones enables the fine tuning of the maximum emission without significantly reducing the luminescence quantum yield. The maximum quantum yield value of 62.6% for derivatives based on 2,1,3-benzoxadiazole (1a) in cyclohexane was achieved. Two devices with the architecture of glass/ITO/PEDOT-PSS/poly-TPD/EML/TPBi/LiF/Al (EML = emitting layer) were fabricated to check the suitability of the synthesized compounds as a single active emission layer in OLED. These OLEDs exhibited clear red electroluminescence of the dyes with the maximum current efficiency of 0.85 Cd/A.
The T3SS Effector Protease NleC Is Active within Citrobacter rodentium
Authors: Hasan Md Kamrul , El Qaidi Samir , Hardwidge Philip R.
Published: May 2021

Whether type III secretion system (T3SS) effector proteins encoded by Gram-negative bacterial pathogens have intra-bacterial activities is an important and emerging area of investigation. Gram-negative bacteria interact with their mammalian hosts by using secretion systems to inject virulence proteins directly into infected host cells. Many of these injected protein effectors are enzymes that modify the structure and inhibit the function of mammalian proteins. The underlying dogma is that T3SS effectors are inactive until they are injected into host cells, where they then fold into their active conformations. We previously observed that the T3SS effectors NleB and SseK1 glycosylate Citrobacter rodentium and Salmonella enterica proteins, respectively, leading to enhanced resistance to environmental stress. Here, we sought to extend these studies to determine whether the T3SS effector protease NleC is also active within C. rodentium. To do this, we expressed the best-characterized mammalian substrate of NleC, the NF-κB p65 subunit in C. rodentium and monitored its proteolytic cleavage as a function of NleC activity. Intra-bacterial p65 cleavage was strictly dependent upon NleC. A p65 mutant lacking the known CE cleavage motif was resistant to NleC. Thus, we conclude that, in addition to NleB, NleC is also enzymatically active within C. rodentium.