bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Neck Circumference, Waist Circumference, and Skinfold Thickness in Measuring the Subcutaneous Fat Distribution and Their Association with Handgrip Strength: Cross-Sectional Study
Authors: Asiri Faisal , Dixit Snehil , Alsubaie Saud F. , Gular Kumar , Alshahrani Adel , Reddy Ravi Shankar , Gautam Ajay Prashad , Tedla Jaya Shanker
Published: November 2022

Skinfold measurement (SKF) can accurately measure abdominal obesity and is regarded as a surrogate marker to predict non-communicable diseases. The objective of the present study was to observe the degree of association between neck circumference (NC), SKF and handgrip strength (HGS). Secondly, also to know the effects of smoking on NC, HGS and SKF. The mean and standard deviations and frequencies in percentage were analyzed, respectively. The degree of association between NC, anthropometric characters and HGS was also analyzed using the Pearson correlation. Furthermore, multiple linear regression models were used to study the degree of influence of independent variables on dependent variables. Correlation assessment for neck circumference with waist circumference and HGS revealed a weak association. While with SKF for four sites, a strong association was found. A significant regression was found among the smokers in the model (F (2, 7) = 5.2, p-value of 0.04 with an R2 of 0.598). The predictor variables, like waist and NC, can produce a variation of 59.8% in the dependent variable. Whereas, among non-smokers, an insignificant regression was seen. In conclusion, neck circumference is associated with SKF. However, a small sample size of young smokers revealed that NC and waist circumference influenced HGS.
Is HIV Pre-Exposure Prophylaxis among Men Who Have Sex with Men Effective in a Real-World Setting? Experience with One-On-One Counseling and Support in a Sexual Health Center in Paris, 2018–2020
Authors: Thomas Bérenger , Piron Prescillia , de La Rochebrochard Elise , Segouin Christophe , Troude Pénélope
Published: November 2022

HIV pre-exposure prophylaxis (PrEP) is highly effective but depends on patients’ care engagement, which is often mediocre and poorly measured in real-world settings. This study aimed to assess the effectiveness of a PrEP program in a sexual health center that included accompanying measures to improve engagement. A retrospective observational study was conducted. All men who have sex with men (MSM) who initiated PrEP for the first time between 1 August 2018 and 30 June 2019 in the Fernand-Widal sexual health center, Paris, France, were included. Among the 125 MSM who initiated PrEP, the median age was 33 and most had only male partners. At initiation, 58% were considered at very high risk of HIV infection, mainly due to a history of post-exposure prophylaxis. During the first year, patients attended a median of three visits (Q1–Q3, 2–4). At 12 months, 96% (95% CI, 92.6 to 99.4) had a successful PrEP course, assessed by a novel metric. These results highlight the possibility of achieving a high PrEP success ratio among MSM in a real-world setting. The accompanying measures and one-on-one counseling by a trained counselor could explain the effectiveness of this PrEP program.
Intravitreal Vascular Endothelial Growth Factor Inhibitor Use and Renal Function Decline in Patients with Diabetic Retinopathy
Authors: Ou Shih-Hsiang , Yin Chun-Hao , Chung Tung-Ling , Chen Hsin-Yu , Chen Chien-Liang , Chen Jin-Shuen , Lee Po-Tsang
Published: November 2022

Adverse renal effects of systemic vascular endothelial growth factor (VEGF) inhibitor treatment are well documented. We aimed to identify associations between intravitreal VEGF inhibitor use and renal function decline in patients with diabetic retinopathy. We included 625 patients with diabetic retinopathy for regular renal function follow-ups and grouped them according to intravitreal therapy (67 with and 558 without treatment). We used a generalized estimating equation model to identify renal function decline risk factors. Increased age (p = 0.02), insulin use (p = 0.01), hypertension (p < 0.01), and ischemic heart disease (p < 0.01) were associated with significantly decreased estimated glomerular filtration rates (eGFRs) in patients with diabetic retinopathy after 1-year follow-up. Compared to the control group, patients who received intravitreal VEGF inhibitor injections showed a declining eGFR trend in the repeated measurement model without statistical significance (p = 0.06). In subgroup analysis, patients with initial eGFR ≤ 30 mL/min/1.73 m2 who received intravitreal VEGF inhibitors had significantly decreased renal function (p < 0.01) compared to those without treatment. Intravitreal VEGF inhibitor injection was associated with renal function deterioration among patients with diabetic retinopathy and advanced chronic kidney disease. Strategies to monitor renal function after treatment should be considered in these high-risk populations.
Psychological Research on Sleep Problems and Adjustment of Working Hours during Teleworking in the COVID-19 Pandemic: An Exploratory Study
Authors: Figueiredo Sandra , João Raquel , Alho Laura , Hipólito João
Published: November 2022

Mandatory home isolation caused by COVID-19 in professional contexts led to a situation that required work activities to be converted into a remote modality. The literature on this topic is very recent, given the pandemic and the uncertainty of virtual and face-to-face work modalities. This study aimed to examine the effects of adults’ prolonged exposure to screens on sleep quality, the type of devices used according to age and gender, periods of access to such devices and the impact on performance in the context of telework due to COVID-19. Specifically, the study analyzed the differences in the use of devices and in the time spent using them during and after teleworking between genders and age groups. A total of 127 Portuguese participants answered the Pittsburgh Sleep Quality Index and a questionnaire that we specifically developed to characterize teleworking habits. The results showed differences between men and women regarding the use of devices and its impact on sleep quality, as well as differences in terms of age. These results are discussed in terms of how the current work context may affect performance, sleep, gender differences and the adverse effects of exposure to screens during and after work hours.
Bullying and Emotional Problems in Pupils from 11 to 13 Years Old: Joint Detection through Self-Report
Authors: González-Contreras Ana-Isabel , Ramos-Sánchez José-Luis
Published: November 2022

The objective of this study was to adapt and make available a valid instrument based on a joint questionnaire (self-report type) to detect the risk of bullying and emotional problems in pupils aged from 11 to 13 years. The questionnaires used were that of Spain’s Ombudsman (Defensor del Pueblo) to detect the risk of becoming a victim of bullying and an adaptation of Spain’s CECAD to assess the risk of emotional problems. The participants were 1077 gender-matched subjects enrolled in the 6th year of Primary Education (n = 467) and the 1st year of Lower Secondary Education (n = 610) from 19 schools in the Region of Extremadura. High reliability was obtained in both questionnaires, as well as a significant relationship between bullying and emotional problems (0.36). The scales place the pupils at either a certain risk level (mild, moderate, or severe) or no risk. The study concludes with the description of four situations deriving from the cross relationship between victimization and the pupil’s emotional problems: (1) no risk of bullying and no risk of emotional problems (73.2%), (2) risk of bullying but no risk of emotional problems (11.1%), (3) no risk of bullying but risk of emotional problems (9.4%), and (4) risk of bullying and risk of emotional problems (6.3%).
The Genetics of Risk Aversion: A Systematic Review
Authors: Molins Francisco , Sahin Fatmanur , Serrano Miguel
Published: November 2022

Risk and loss aversion are phenomena with an important influence on decision-making, especially in economic contexts. At present, it remains unclear whether both are related, as well as whether they could have an emotional origin. The objective of this review, following the PRISMA statements, is to find consistencies in the genetic bases of risk and loss aversion with the aim of understanding their nature and shedding light on the above issues. A total of 23 empirical research met the inclusion criteria and were included from PubMed and ScienceDirect. All of them reported genetic measures from human samples and studied risk and loss aversion within an economic framework. The results for risk aversion, although with many limitations, attributed mainly to their heterogeneity and the lack of control in the studies, point to the implication of multiple polymorphisms related to the regulation of the serotonergic and dopaminergic pathways. In general, studies found the highest levels of risk aversion were associated with alleles that are linked to lower (higher) sensitivity or levels of dopamine (serotonin). For loss aversion, the scarcity of results prevents us from drawing clear conclusions, although the limited evidence seems to point in the same direction as for risk aversion. Therefore, it seems that risk aversion could have a stable genetical base which, in turn, is closely linked to emotions, but more research is needed to answer whether this phenomenon is related to loss aversion, as well as if the latter could also have an emotional origin. We also provide recommendations for future studies on genetics and economic behavior.
Factors Influencing Depressive Symptoms in Middle-Aged South Korean Workers by Job Type: A Population-Based Study
Authors: Kwon Myoungjin , Ahn Sung Yun , Kim Sun Ae
Published: November 2022

Depressive symptoms can be influenced by different factors, including job types. In this study, we identified factors that affect depressive symptoms among South Korean workers by job type using data from the Korea National Health and Nutrition Examination Survey. Examined respondents were between 40 and 69 years (N = 9375). A complex sample linear regression analysis revealed various significant factors based on job type. For office workers, the number of household members, health-related quality of life, diabetes, sitting time, subjective health, and stress were significant influencing factors for depressive symptoms (explanatory power of 23.2%) (p < 0.001). For service workers, gender, health-related quality of life, food intake, aerobic exercise, sitting time, subjective health, and stress were significant influencing factors for depressive symptoms (explanatory power of 49.6%) (p < 0.001). For labor workers, gender, type of living, health-related quality of life, BMI, weight change, weight control, aerobic exercise, diabetes, subjective health, and stress were significant influencing factors for depressive symptoms (explanatory power of 35.8%) (p < 0.001). These differences highlight the need for customized programs targeted at each job type to maintain and promote mental health among workers.
The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome
Authors: Tomczyk-Socha Martyna , Tomczak Wojciech , Turno-Kręcicka Anna
Published: November 2022

Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with genetic and environmental risk factors. The aim of this manuscript was to analyze miR expression in PEX. In recent years, an attempt has been made to investigate and describe the level of expression of selected miRs in PEX. Four polymorphisms of genes isolated from the blood that may be related to PEX were identified and miR-122-5p was found to be upregulated in patient blood. Furthermore, 18 miRs were identified with a statistically different expression in the aqueous humor. A significantly elevated expression of miR-125b was found in the anterior lens capsule, and four miRs were described, which may have a significant impact on the development of PEX. Regulatory miR molecules are gaining more and more importance in research aimed at identifying and isolating molecular markers related to the pathogenesis and prognosis of PEX, but further studies are needed.
Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer
Authors: Shinohara Hajime , Kobayashi Maki , Hayashi Kumiko , Nogawa Daichi , Asakawa Ayaka , Ohata Yae , Kubota Kazuishi , Takahashi Hisashi , Yamada Miyuki , Tokunaga Masanori , Kinugasa Yusuke , Oda Goshi , Nakagawa Tsuyoshi , Onishi Iichiroh , Kinowaki Yuko , Kurata Morito , Ohashi Kenichi , Kitagawa Masanobu , Yamamoto Kouhei
Published: November 2022

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.
Investigating Grapevine Red Blotch Virus Infection in Vitis vinifera L. cv. Cabernet Sauvignon Grapes: A Multi-Omics Approach
Authors: Rumbaugh Arran C. , Durbin-Johnson Blythe , Padhi Emily , Lerno Larry , Cauduro Girardello Raul , Britton Monica , Slupsky Carolyn , Sudarshana Mysore R. , Oberholster Anita
Published: November 2022

Grapevine red blotch virus (GRBV) is a recently identified virus. Previous research indicates primarily a substantial impact on berry ripening in all varieties studied. The current study analyzed grapes’ primary and secondary metabolism across grapevine genotypes and seasons to reveal both conserved and variable impacts to GRBV infection. Vitis vinifera cv. Cabernet Sauvignon (CS) grapevines grafted on two different rootstocks (110R and 420A) were analyzed in 2016 and 2017. Metabolite profiling revealed a considerable impact on amino acid and malate acid levels, volatile aroma compounds derived from the lipoxygenase pathway, and anthocyanins synthesized in the phenylpropanoid pathway. Conserved transcriptional responses to GRBV showed induction of auxin-mediated pathways and photosynthesis with inhibition of transcription and translation processes mainly at harvest. There was an induction of plant-pathogen interactions at pre-veraison, for all genotypes and seasons, except for CS 110R in 2017. Lastly, differential co-expression analysis revealed a transcriptional shift from metabolic synthesis and energy metabolism to transcription and translation processes associated with a virus-induced gene silencing transcript. This plant-derived defense response transcript was only significantly upregulated at veraison for all genotypes and seasons, suggesting a phenological association with disease expression and plant immune responses.
Ouabain-Induced Changes in the Expression of Voltage-Gated Potassium Channels in Epithelial Cells Depend on Cell–Cell Contacts
Authors: Cereijido Marcelino , Jimenez Lidia , Hinojosa Lorena , Castillo Aida , Martínez-Rendon Jacqueline , Ponce Arturo
Published: November 2022

Ouabain is a cardiac glycoside, initially isolated from plants, and currently thought to be a hormone since some mammals synthesize it endogenously. It has been shown that in epithelial cells, it induces changes in properties and components related to apical–basolateral polarity and cell–cell contacts. In this work, we used a whole-cell patch clamp to test whether ouabain affects the properties of the voltage-gated potassium currents (Ik) of epithelial cells (MDCK). We found that: (1) in cells arranged as mature monolayers, ouabain induced changes in the properties of Ik; (2) it also accelerated the recovery of Ik in cells previously trypsinized and re-seeded at confluence; (3) in cell–cell contact-lacking cells, ouabain did not produce a significant change; (4) Na+/K+ ATPase might be the receptor that mediates the effect of ouabain on Ik; (5) the ouabain-induced changes in Ik required the synthesis of new nucleotides and proteins, as well as Golgi processing and exocytosis, as evidenced by treatment with drugs inhibiting those processes; and (5) the signaling cascade included the participation of cSrC, PI3K, Erk1/2, NF-κB and β-catenin. These results reveal a new role for ouabain as a modulator of the expression of voltage-gated potassium channels, which require cells to be in contact with themselves.
Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)2, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2)
Authors: Chong Tsz Cheung , Wong Iris L. K. , Cui Jiahua , Law Man Chun , Zhu Xuezhen , Hu Xuesen , Kan Jason W. Y. , Yan Clare S. W. , Chan Tak Hang , Chow Larry M. C.
Published: November 2022

Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer Ac15(Az8)2 was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC50 for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that Ac15(Az8)2 restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg of Ac15(Az8)2 resulted in plasma concentration above its EC50 (72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest that Ac15(Az8)2 is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.
Crystal Structure and Biochemical Analysis of a Cytochrome P450 CYP101D5 from Sphingomonas echinoides
Authors: Subedi Pradeep , Do Hackwon , Lee Jun Hyuck , Oh Tae-Jin
Published: November 2022

Cytochrome P450 enzymes (CYPs) are heme-containing enzymes that catalyze hydroxylation with a variety of biological molecules. Despite their diverse activity and substrates, the structures of CYPs are limited to a tertiary structure that is similar across all the enzymes. It has been presumed that CYPs overcome substrate selectivity with highly flexible loops and divergent sequences around the substrate entrance region. Here, we report the newly identified CYP101D5 from Sphingomonas echinoides. CYP101D5 catalyzes the hydroxylation of β-ionone and flavonoids, including naringenin and apigenin, and causes the dehydrogenation of α-ionone. A structural investigation and comparison with other CYP101 families indicated that spatial constraints at the substrate-recognition site originate from the B/C loop. Furthermore, charge distribution at the substrate binding site may be important for substrate selectivity and the preference for CYP101D5.
A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients
Authors: Xu Qi , Kaur Jaspreet , Wylie Dennis , Mittal Karuna , Li Hongxiao , Kolachina Rishab , Aleskandarany Mohammed , Toss Michael S. , Green Andrew R. , Yang Jianchen , Yankeelov Thomas E. , Bhattarai Shristi , Janssen Emiel A. M. , Kong Jun , Rakha Emad A. , Kowalski Jeanne , Aneja Ritu
Published: November 2022

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2–4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance.
Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice
Authors: Yang Yang , Chen Hui , Wan Yue , Dong Diandian , Wang Xiaofang , Yao Songhui , Wang Pengjun , Xiang Shensi , Yang Xiaoming , Yu Miao
Published: November 2022

Hepassocin (HPS) is a hepatokine that has multiple proposed physiological functions. Some of the biological processes in which it is involved are closely related to endoplasmic reticulum (ER) stress, but the role of HPS in the regulation of ER stress remains unclear. Here, we demonstrated that HPS transcription is induced by the protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4) cascade upon ER stress in hepatocytes. Additionally, fasting/refeeding also induced HPS expression in mice liver. The loss of HPS sensitizes hepatocytes to ER stress-related cytotoxicity in vitro, whereas HPS treatment altered these phenotypes. HPS deficiency exacerbates fasting/refeeding-induced ER stress in vivo. The preliminary administration of HPS ameliorates liver steatosis, cell death, and inflammation in mice injected with tunicamycin (TM). The improvement of HPS can be observed even if HPS protein is injected after TM treatment. Furthermore, the administration of an ER stress inhibitor alleviated steatohepatitis in methionine- and choline-deficient (MCD) diet-fed HPS-deficient mice. These results suggest that HPS protects hepatocytes from physiological and pathological ER stress, and that the inactivation of HPS signaling aggravating ER stress may be a novel mechanism that drives the development of steatohepatitis. The protective mechanism of HPS against ER stress in hepatocytes was associated with the regulation of ER calcium handling, and the suppression of calcium influx release from ER upon stressor treatment. Collectively, our findings indicate that HPS may act in a negative feedback fashion to regulate hepatic ER stress and protect hepatocytes from ER stress-related injury. HPS has the potential to be a candidate drug for the treatment of ER stress-related liver injury.
The Association between Cyclin Dependent Kinase 2 Associated Protein 1 (CDK2AP1) and Molecular Subtypes of Lethal Prostate Cancer
Authors: Gamallat Yaser , Bakker Andrea , Khosh Kish Ealia , Choudhry Muhammad , Walker Simon , Aldakheel Saood , Seyedi Sima , Huang Kuo-Cheng , Ghosh Sunita , Gotto Geoffrey , Bismar Tarek A.
Published: November 2022

Prostate cancer (PCa) is one of the most commonly diagnosed types of malignancy and is the second leading cause of cancer-related death in men in developed countries. Cyclin dependent kinase 2 associate protein 1(CDK2AP1) is an epigenetic and cell cycle regulator gene which has been downregulated in several malignancies, but its involvement in PCa has not yet been investigated in a clinical setting. We assessed the prognostic value of CDK2AP1 expression in a cohort of men diagnosed with PCa (n = 275) treated non-surgically by transurethral resection of the prostate (TURP) and studied the relationship between CDK2AP1 expression to various PCa molecular subtypes (ERG, PTEN, p53 and AR) and evaluated the association with clinical outcome. Further, we used bioinformatic tools to analyze the available TCGA PRAD transcriptomic data to explore the underlying mechanism. Our data confirmed increased expression of CDK2AP1 with higher Gleason Grade Group (GG) and metastatic PCa (p <0.0001). High CDK2AP1 expression was associated with worse overall survival (OS) (HR: 1.62, CI: 1.19–2.21, p = 0.002) and cause-specific survival (CSS) (HR: 2.012, CI 1.29–3.13, p = 0.002) using univariate analysis. When compared to each sub-molecular type. High CDK2AP1/PTEN-loss, abnormal AR or p53 expression showed even worse association to poorer OS and CCS and remained significant when adjusted for GG. Our data indicates that CDK2AP1 directly binds to p53 using the Co-Immunoprecipitation (Co-IP) technique, which was validated using molecular docking tools. This suggests that these two proteins have a significant association through several binding features and correlates with our observed clinical data. In conclusion, our results indicated that the CDK2AP1 overexpression is associate with worse OS and CSS when combined with certain PCa molecular subtypes; interaction between p53 stands out as the most prominent candidate which directly interacts with CDK2AP1.
Potential Focal Adhesion Kinase Inhibitors in Management of Cancer: Therapeutic Opportunities from Herbal Medicine
Authors: Chen Feiyu , Zhong Zhangfeng , Zhang Cheng , Lu Yuanjun , Chan Yau-Tuen , Wang Ning , Zhao Di , Feng Yibin
Published: November 2022

Focal adhesion kinase (FAK) is a multifunctional protein involved in cellular communication, integrating and transducing extracellular signals from cell-surface membrane receptors. It plays a central role intracellularly and extracellularly within the tumor microenvironment. Perturbations in FAK signaling promote tumor occurrence and development, and studies have revealed its biological behavior in tumor cell proliferation, migration, and adhesion. Herein we provide an overview of the complex biology of the FAK family members and their context-dependent nature. Next, with a focus on cancer, we highlight the activities of FAK signaling in different types of cancer and how knowledge of them is being used for screening natural compounds used in herbal medicine to fight tumor development.
GWAS of Reproductive Traits in Large White Pigs on Chip and Imputed Whole-Genome Sequencing Data
Authors: Wang Xiaoqing , Wang Ligang , Shi Liangyu , Zhang Pengfei , Li Yang , Li Mianyan , Tian Jingjing , Wang Lixian , Zhao Fuping
Published: November 2022

Total number born (TNB), number of stillborn (NSB), and gestation length (GL) are economically important traits in pig production, and disentangling the molecular mechanisms associated with traits can provide valuable insights into their genetic structure. Genotype imputation can be used as a practical tool to improve the marker density of single-nucleotide polymorphism (SNP) chips based on sequence data, thereby dramatically improving the power of genome-wide association studies (GWAS). In this study, we applied Beagle software to impute the 50 K chip data to the whole-genome sequencing (WGS) data with average imputation accuracy (R2) of 0.876. The target pigs, 2655 Large White pigs introduced from Canadian and French lines, were genotyped by a GeneSeek Porcine 50K chip. The 30 Large White reference pigs were the key ancestral individuals sequenced by whole-genome resequencing. To avoid population stratification, we identified genetic variants associated with reproductive traits by performing within-population GWAS and cross-population meta-analyses with data before and after imputation. Finally, several genes were detected and regarded as potential candidate genes for each of the traits: for the TNB trait: NOTCH2, KLF3, PLXDC2, NDUFV1, TLR10, CDC14A, EPC2, ORC4, ACVR2A, and GSC; for the NSB trait: NUB1, TGFBR3, ZDHHC14, FGF14, BAIAP2L1, EVI5, TAF1B, and BCAR3; for the GL trait: PPP2R2B, AMBP, MALRD1, HOXA11, and BICC1. In conclusion, expanding the size of the reference population and finding an optimal imputation strategy to ensure that more loci are obtained for GWAS under high imputation accuracy will contribute to the identification of causal mutations in pig breeding.
Recognition of a Clickable Abasic Site Analog by DNA Polymerases and DNA Repair Enzymes
Authors: Endutkin Anton V. , Yudkina Anna V. , Zharkov Timofey D. , Kim Daria V. , Zharkov Dmitry O.
Published: November 2022

Azide–alkyne cycloaddition (“click chemistry”) has found wide use in the analysis of molecular interactions in living cells. 5-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol (EAP) is a recently developed apurinic/apyrimidinic (AP) site analog functionalized with an ethynyl moiety, which can be introduced into cells in DNA constructs to perform labeling or cross-linking in situ. However, as a non-natural nucleoside, EAP could be subject to removal by DNA repair and misreading by DNA polymerases. Here, we investigate the interaction of this clickable AP site analog with DNA polymerases and base excision repair enzymes. Similarly to the natural AP site, EAP was non-instructive and followed the “A-rule”, directing residual but easily detectable incorporation of dAMP by E. coli DNA polymerase I Klenow fragment, bacteriophage RB69 DNA polymerase and human DNA polymerase β. On the contrary, EAP was blocking for DNA polymerases κ and λ. EAP was an excellent substrate for the major human AP endonuclease APEX1 and E. coli AP exonucleases Xth and Nfo but was resistant to the AP lyase activity of DNA glycosylases. Overall, our data indicate that EAP, once within a cell, would represent a replication block and would be removed through an AP endonuclease-initiated long-patch base excision repair pathway.
Rethinking the Dilated Encoder in TE-YOLOF: An Approach Based on Attention Mechanism to Improve Performance for Blood Cell Detection
Authors: Xu Fanxin , Lyu He , Xiang Wei
Published: November 2022

Blood cell detection is an essential branch of microscopic imaging for disease diagnosis. TE-YOLOF is an effective model for blood cell detection, and was recently found to have an outstanding trade-off between accuracy and model complexity. However, there is a lack of understanding of whether the dilated encoder in TE-YOLOF works well for blood cell detection. To address this issue, we perform a thorough experimental analysis and find the interesting fact that the dilated encoder is not necessary for TE-YOLOF to perform the blood cell detection task. For the purpose of increasing performance on blood cell detection, in this research, we use the attention mechanism to dominate the dilated encoder place in TE-YOLOF and find that the attention mechanism is effective to address this problem. Based upon these findings, we propose a novel approach, named Enhanced Channel Attention Module (ECAM), based on attention mechanism to achieve precision improvement with less growth on model complexity. Furthermore, we examine the proposed ECAM method compared with other tip-top attention mechanisms and find that the proposed attention method is more effective on blood cell detection task. We incorporate the spatial attention mechanism in CBAM with our ECAM to form a new module, which is named Enhanced-CBAM. We propose a new network named Enhanced Channel Attention Network (ENCANet) based upon Enhanced-CBAM to perform blood cell detection on BCCD dataset. This network can increase the accuracy to 90.3 AP while the parameter is only 6.5 M. Our ENCANet is also effective for conducting cross-domain blood cell detection experiments.
Helminths and Bacterial Microbiota: The Interactions of Two of Humans’ “Old Friends”
Authors: Llinás-Caballero Kevin , Caraballo Luis
Published: November 2022

Humans have coexisted with helminths and bacteria for the entire existence of our species. Nowadays, helminth infections affect more than 1.9 billion people worldwide, especially in underdeveloped regions that lack optimal sanitary conditions. In addition, commensal microorganisms inhabit several compartments of humans, including the gastrointestinal tract, constituting what we know as the microbiota. Helminths and bacterial microbiota can interact in various ways. In this review, the interactions between helminths and commensal bacteria are analyzed in both animal models and humans. In developing countries, the gut microbiota exhibits high diversity, which could be linked to the high burden of helminthiasis in these areas. In fact, several studies show that helminth infections are associated with an increased gut microbiota diversity and changes in its composition. Interestingly, these changes can modify the risk for some diseases, such as asthma, colitis, viral infections, and metabolic conditions. Besides, the microbiota is necessary for the establishment of some helminth infections and can also influence the evolution of these diseases. Specific bacterial taxa can contribute to the resistance or susceptibility to certain helminths. The mechanisms underlying helminth–microbiota interactions are not completely understood. More research is necessary to address this and other unmet needs, especially considering that available studies are heterogeneous and sometimes yield conflicting results.
Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1
Authors: De Serres-Bérard Thiéry , Ait Benichou Siham , Jauvin Dominic , Boutjdir Mohamed , Puymirat Jack , Chahine Mohamed
Published: November 2022

Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3′ UTR of the myotonic dystrophy protein kinase (DMPK) gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.
Proteomic Profiling Revealed Mitochondrial Dysfunction in Photoreceptor Cells under Hyperglycemia
Authors: Lam Christie Hang-I , Cheung Jimmy Ka-Wai , Tse Dennis Yan-Yin , Lam Thomas Chuen
Published: November 2022

Diabetic retinopathy (DR) was identified as a leading cause of blindness and vision impairment in 2020. In addition to vasculopathy, DR has been found to involve retinal neurons, including amacrine cells and retinal ganglion cells. Despite possessing features that are susceptible to diabetic conditions, photoreceptor cells have received relatively little attention with respect to the development of DR. Until recently, studies have suggested that photoreceptors secret proinflammatory molecules and produce reactive oxygen species that contribute to the development of DR. However, the effect of hyperglycemia on photoreceptors and its underlying mechanism remains elusive. In this study, the direct effect of high glucose on photoreceptor cells was investigated using a 661w photoreceptor-like cell line. A data-independent sequential window acquisition of all theoretical mass spectra (SWATH)-based proteomic approach was employed to study changes induced by high glucose in the proteomic profile of the cells. The results indicated that high glucose induced a significant increase in apoptosis and ROS levels in the 661w cells, with mitochondrial dysfunction among the major affected canonical pathways. The involvement of mitochondrial dysfunction was further supported by increased mitochondrial fission and reduced mitochondrial bioenergetics. Collectively, these findings provide a biological basis for a possible role of photoreceptors in the pathogenesis of DR.
Preinitiation Complex Loading onto mRNAs with Long versus Short 5′ TLs
Authors: Weiss Benjamin , Jaquier-Gubler Pascale , Curran Joseph Alphonsus
Published: November 2022

The first step in translation initiation consists in the recruitment of the small ribosome onto the mRNA. This preinitiation complex (PIC) loads via interactions with eIF4F that has assembled on the 5′ cap. It then scans the 5′ TL (transcript leader) to locate a start site. The molecular architecture of the PIC-mRNA complex over the cap is beginning to be resolved. As part of this, we have been examining the role of the 5′ TL length. We observed in vivo initiation events on AUG codons positioned within 3 nts of the 5′ cap and robust initiation in vitro at start sites immediately downstream of the 5′ end. Ribosomal toe-printing confirmed the positioning of these codons within the P site, indicating that the ribosome reads from the +1 position. To explore differences in the eIF4E-5′ cap interaction in the context of long versus short TL, we followed the fate of the eIF4E-cap interaction using a novel solid phase in vitro expression assay. We observed that ribosome recruitment onto a short TL disrupts the eIF4E-cap contact releasing all the mRNA from the solid phase, whereas with a long the mRNA distributes between both phases. These results are discussed in the context of current recruitment models.
Gonadal Sex Differentiation and Ovarian Organogenesis along the Cortical–Medullary Axis in Mammals
Authors: Imaimatsu Kenya , Uchida Aya , Hiramatsu Ryuji , Kanai Yoshiakira
Published: November 2022

In most mammals, the sex of the gonads is based on the fate of the supporting cell lineages, which arises from the proliferation of coelomic epithelium (CE) that surfaces on the bipotential genital ridge in both XY and XX embryos. Recent genetic studies and single-cell transcriptome analyses in mice have revealed the cellular and molecular events in the two-wave proliferation of the CE that produce the supporting cells. This proliferation contributes to the formation of the primary sex cords in the medullary region of both the testis and the ovary at the early phase of gonadal sex differentiation, as well as to that of the secondary sex cords in the cortical region of the ovary at the perinatal stage. To support gametogenesis, the testis forms seminiferous tubules in the medullary region, whereas the ovary forms follicles mainly in the cortical region. The medullary region in the ovary exhibits morphological and functional diversity among mammalian species that ranges from ovary-like to testis-like characteristics. This review focuses on the mechanism of gonadal sex differentiation along the cortical-medullary axis and compares the features of the cortical and medullary regions of the ovary in mammalian species.
A Novel Deep Transfer Learning Approach Based on Depth-Wise Separable CNN for Human Posture Detection
Authors: Ogundokun Roseline Oluwaseun , Maskeliūnas Rytis , Misra Sanjay , Damasevicius Robertas
Published: November 2022

Human posture classification (HPC) is the process of identifying a human pose from a still image or moving image that was recorded by a digicam. This makes it easier to keep a record of people’s postures, which is helpful for many things. The intricate surroundings that are depicted in the image, such as occlusion and the camera view angle, make HPC a difficult process. Consequently, the development of a reliable HPC system is essential. This study proposes the “DeneSVM”, an innovative deep transfer learning-based classification model that pulls characteristics from image datasets to detect and classify human postures. The paradigm is intended to classify the four primary postures of lying, bending, sitting, and standing. These positions are classes of sitting, bending, lying, and standing. The Silhouettes for Human Posture Recognition dataset has been used to train, validate, test, and analyze the suggested model. The DeneSVM model attained the highest test precision (94.72%), validation accuracy (93.79%) and training accuracy (97.06%). When the efficiency of the suggested model was validated using the testing dataset, it too had a good accuracy of 95%.
Upper-Arm SBP Decline Associated with Repeated Cuff-Oscillometric Inflation Significantly Correlated with the Arterial Stiffness Index
Authors: Kawaura Noriyuki , Nakashima-Sasaki Rie , Doi Hiroshi , Uchida Kotaro , Sugawara Takuya , Saigo Sae , Abe Kaito , Arakawa Kentaro , Tamura Koichi , Hibi Kiyoshi , Ishigami Tomoaki
Published: November 2022

We evaluated the clinical significance of the new non-invasive vascular indices to explore their potential utility using repeated cuff-oscillometric inflation. In 250 consecutive outpatients, we performed a cross-sectional, retrospective, single-center, observational study to investigate sequential differences in arterial stiffness using blood pressure, arterial velocity pulse index (AVI), and arterial pressure volume index (API) with repeated measurements. Males accounted for 62.7% of the patients, and the mean age was 68.1 ± 12.1 years. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the first reading in repeated measurements were 133.07 ± 21.20 mmHg and 73.94 ± 13.56 mmHg, respectively. The mean AVI and API were 23.83 ± 8.30 and 31.12 ± 7.86, respectively. In each measurement of these parameters, although DBP and AVI did not show significant changes throughout repeated measurements, SBP and API decreased significantly according to the measurement orders. Furthermore, changes in SBP and API were significantly correlated in several of the models. In this study, it was concluded that upper-arm SBP decline associated with repeated cuff-oscillometric inflation was significantly correlated with the arterial stiffness index. The findings of this study will allow clinicians to easily recognize the progression of atherosclerosis through regular, routine practice. In conclusion, this study suggests that changes in repeated SBP measurements may be predictive of arterial stiffness and atherosclerosis.
PEGylated Strontium Sulfite Nanoparticles with Spontaneously Formed Surface-Embedded Protein Corona Restrict Off-Target Distribution and Accelerate Breast Tumour-Selective Delivery of siRNA
Authors: Karim Md. Emranul , Chowdhury Ezharul Hoque
Published: November 2022

As transporters of RNAi therapeutics in preclinical and clinical studies, the application of nanoparticles is often hindered by their susceptibility to opsonin-mediated clearance, poor biological stability, ineffectual targeting, and undesirable effects on healthy cells. Prolonging the blood circulation time while minimizing the off-target distribution and associated toxicity is indispensable for the establishment of a clinically viable delivery system for therapeutic small interfering RNAs (siRNAs). Herein, we report a scalable and straightforward approach to fabricate non-toxic and biodegradable pH-responsive strontium sulfite nanoparticles (SSNs) wrapped with a hydrophilic coating material, biotinylated PEG to lessen unforeseen biological interactions. Surface functionalization of SSNs with PEG led to the generation of small and uniformly distributed particles with a significant affinity towards siRNAs and augmented internalization into breast cancer cells. A triple quadrupole liquid chromatography-mass spectrometry (LC-MS) was deployed to identify the proteins entrapped onto the SSNs, with the help of SwissProt.Mus_musculus database. The results demonstrated the reduction of opsonin proteins adsorption owing to the stealth effect of PEG. The distribution of PEGylated SSNs in mice after 4 h and 24 h of intravenous administration in breast tumour-bearing mice was found to be significantly less to the organs of the reticuloendothelial system (RES) and augmented accumulation in the tumour region. The anti-EGFR siRNA-loaded PEG-SSNs exerted a significant inhibitory effect on tumour development in the murine breast cancer model without any significant toxicity to healthy tissues. Therefore, PEGylated SSNs open up a new avenue for tumour-selective efficient delivery of siRNAs in managing breast cancer.
Mixing Properties of Emulsified Fuel Oil from Mixing Marine Bunker-C Fuel Oil and Water
Authors: Lee Taeho , Cho Jinho , Lee Jeekeun
Published: November 2022

Alternative marine fuels are needed to help reduce the exhaust emissions of ships. In this study, we performed an analysis to verify the potential applicability of a fuel based on Bunker-C oil, a low-grade marine heavy oil, as a novel alternative marine fuel. Bunker-C oil and water were mixed in the presence of a 0.8–1.2% emulsifier in four steps from 0% to 25% to produce a special type of emulsified fuel oil. Confocal microscopy images of samples after stabilization for approximately three days at room temperature showed no variation in the pattern at the 0% condition with no water, but a relatively homogenous mixed state of water droplets was found across all domains at the 5–25% conditions. The open-source software Image-J indicated the extraction of 166, 3438, and 5636 water droplets with mean diameters of 1.57, 1.79, and 2.08 μm, as well as maximum diameters of 7.31, 21.41, and 25.91 μm, at the 5%, 15%, and 25% conditions, respectively. For all three conditions, the mean particle diameter was approximately 2 μm, below the 20 μm reported in previous studies, with uniform distributions. This suggests that the mixed state was adequately homogenous.