bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer With Homologous Recombination Deficiency (NANT): Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study
Authors: Zhou Dongchen , Liu Jiahao , Liu Ronghua , Li Huayi , Huang Yi , Ma Ding , Hong Li , Gao Qinglei
Published: March 2022

Background

Ovarian cancer (OC) is a heterogeneous gynecological malignancy with a poor prognosis as the majority of patients are diagnosed at an advanced stage. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for patients who cannot achieve optimal cytoreduction or cannot endure primary debulking surgery (PDS). As there is an increased risk of chemoresistance for platinum-based NACT, it is important to investigate an alternative option. A Poly (ADP-ribose) polymerase inhibitor (PARPi), niraparib, has shown high anti-tumor activity, especially in homologous recombination deficiency (HRD) positive patients with OC. Thus, niraparib as a neoadjuvant treatment agent may help improve surgery accessibility and create survival benefits.

Methods

This multicenter, prospective, single-arm, open-label, phase II study plans to recruit 53 patients (aged 18-75 years) with newly diagnosed HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography [CT] score ≥ 3) International Federation of Gynecology and Obstetrics (FIGO) stage III-IV OC. The HRD status was detected by next-generation sequencing and HRD positive patients will be counseled for study participation. Enrolled patients will receive niraparib capsules QD (200mg or 300mg per day) for two cycles (4 weeks/cycle). After neoadjuvant niraparib treatment, patients exhibiting complete response (CR), partial response (PR), or stable disease (SD) will undergo tumor reduction surgery and subsequent standard carboplatin/paclitaxel-based chemotherapy. The primary objectives include the objective response rate (ORR) and R0 resection rate. The rate of treatment interruption/termination and progression-free survival (PFS) will be secondary objectives. The study uses Simon’s optimal two-stage design (24 and 21 patients for the first and second stage respectively). The data manager will record all adverse events (AEs).

Discussion

This is the first prospective study to evaluate the effectiveness and safety of niraparib in neoadjuvant treatment for advanced OC. The result of this study will provide a solid base for further expanding the clinical applications of the PAPRi and exploring more therapeutic possibilities for patients with HRD positive advanced OC. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04507841.
The Emerging Role of MR Urography in Imaging Megaureters in Children
Authors: Świȩtoń Dominik , Grzywińska Małgorzata , Czarniak Piotr , Gołȩbiewski Andrzej , Durawa Agata , Teodorczyk Jacek , Kaszubowski Mariusz , Piskunowicz Maciej
Published: March 2022

Introduction

Megaureter, described as ureter dilatation more than 7 mm in diameter, commonly associated with other anomalies, is still a diagnostic and therapeutic challenge. Magnetic resonance urography (MRU) appears as a promising method in urinary tract imaging, providing both anatomical and functional information. There are several postprocessing tools to assess renal function (including differential renal function) and severity of ureteral obstruction based on MRU. Still, the place of this method in the diagnostic algorithm of ureteropelvicalyceal dilatation with megaureter remains underestimated. Analysis of imaging findings in a group of children diagnosed with megaureter was done.

Material and Methods

A retrospective analysis of magnetic resonance urography (MRU) was performed in 142 consecutive patients examined from January 2013 to September 2019. Twenty-five patients meeting the criteria of megaureter (dilatation more than 7 mm) in MRU were included in the further analysis. The MRU, ultrasound (US), and scintigraphy results were compared and analyzed together and compared with clinical data.

Results

The sensitivity and specificity of US was comparable to the MRU in the assessment of upper urinary tract morphology (p > 0.05). In five out of 25 children, megaureter was found in each kidney; in a single case, both poles of a duplex kidney were affected. In the diagnosis of ureter ectopia, the MRU was superior to the US for which sensitivity did not exceed 16%. The US showed limited value in the diagnostics of segmental ureter dysplasia as a cause of primary megaureter when compared with MRU. Four cases were visualized in MRU studies, whereas the US examination was negative (all confirmed during surgery). There was a moderate correlation between relative renal function between fMRU and scintigraphy (t = 0.721, p = 0.477) and in the severity of obstruction assessment between both methods (r = 0.441, p < 0.05). However, in 10 kidneys with megaureter, the results in scintigraphy were inconclusive due to the signal from the megaureter imposing on the renal field.

Conclusions

MRU seems to be a preferred method in the diagnostic algorithm for megaureter, providing both anatomical and functional information. MRU is superior to US and scintigraphy in diagnosing urinary tract anomalies with megaureter.
Acceptance Factors for In-Hospital Pharmacist Interventions in Daily Practice: A Retrospective Study
Authors: Durand Amaury , Gillibert André , Membre Sophie , Mondet Lisa , Lenglet Aurélie , Mary Aurélien
Published: March 2022

Introduction: Performing pharmacist interventions (PIs) during the medication review helps to improve the quality of care. The acceptance by the physician of these PIs is a good indicator of the quality of this clinical pharmacy activity. The objective of this study was to determine, in the Amiens-Picardie teaching hospital (France), factors of acceptance in a variable environment of activity (central pharmacy, in the care units, computer assisted).

Methods: All PIs transcribed by pharmacists on the Act-IP© site between November 2018 and April 2019 were analyzed using a complementary search in patient records. The environment, type, and clinical impact on patient health of each PI was collected. Linear mixed-effects models with a random pharmacist intercept were used to investigate the relationship between PI modalities and their chance of being accepted.

Results: A total of 3,100 PIs were traced, of which 2,930 had been followed over time. Of these, 2,930 PIs, 1,504 (51.3%) were performed by a postgraduate pharmacist and 1,426 (48.7%) by a pharmacy resident, 1,623 (55.4%) were performed by verbal exchange, 455 (15.5%) by telephone, 846 (28.9%) by computer software, and 6 (0.2%) by paper. The clinical impact on patient health was major for 976 PIs (33.3%) and vital for 26 PIs (0.9%). According to the Anatomical Therapeutic Chemical Classification (ATC), they were mainly related to anti-infectives (30.3%), the nervous system (18.7%), and blood and blood-forming organs (17.3%). In total, 2,415 PIs (82.4%) were accepted. According to the multivariate model, a PI was more often accepted when it was transmitted orally rather than by software (+27.7%, 95% CI: +23.2 to +32.1%) and when it was transmitted to a medical resident rather than a postgraduate physician (+4.4%, 95% CI: 1.2–7.6%). In these cases, there was a major rather than a moderate clinical impact on patient health (+4.3%, 95% CI: +1.1–+7.6%).

Conclusion: This study highlights the importance of the quality of the exchange with the prescriber and the prioritization of high-risk interventions as key points of medication review to improve rate of pharmacist interventions accepted by physician.
Shexiang Tongxin Dropping Pills Promote Macrophage Polarization-Induced Angiogenesis Against Coronary Microvascular Dysfunction via PI3K/Akt/mTORC1 Pathway
Authors: Lu Xiangyu , Yao Junkai , Li Changxiang , Cui Lingwen , Liu Yizhou , Liu Xiangning , Wang Gang , Dong Jianteng , Deng Qiong , Hu Yueyao , Guo Dongqing , Wang Wei , Li Chun
Published: March 2022

Background: Accumulating evidence suggests that coronary microvascular dysfunction (CMD) is one of the important causes of coronary artery diseases. Angiogenesis can effectively improve CMD by increasing blood supply capacity, recovering cardiac function and poor hemodynamics. Clinical studies have approved Shexiang Tongxin dropping pill (STDP), which has exerted remarkable roles on ameliorating CMD, but the effects and mechanisms of STDPs on angiogenesis have not been clarified.

Purpose: The purpose of this study was to elucidate the effects and potential mechanisms of STDPs on macrophage polarization-induced angiogenesis against CMD.

Methods: Echocardiography, optical microangiography (OMAG), and histological examination were applied to evaluate cardioprotection and proangiogenic effects of STDPs on left anterior descending (LAD) ligation-induced CMD rats. In vitro, oxygen–glucose deprivation–reperfusion (OGD/R)-induced HUVEC model and LPS-stimulated bone marrow-derived macrophage (BMDM) model were established to observe the effects of STDPs on angiogenesis and M2 macrophage polarization.

Results: STDPs improved cardiac function, increased microvascular density, and the number of M2 macrophages in the heart of CMD rats. In vitro, STDPs accelerated the proliferation, migration, and tube formation in OGD/R-induced HUVECs similar to the effects of VEGF-A. Furthermore, in LPS-stimulated BMDMs model, STDPs modulated M2 macrophage polarization and increased VEGF-A release via the PI3K/AKT/mTORC1 pathway.

Conclusion: STDPs promoted macrophage polarization-induced angiogenesis against CMD via the PI3K/Akt/mTORC1 pathway. Our results demonstrated that the phenotype transformation of macrophages and stimulating the secretion of VEGF-A may be applied as novel cardioprotective targets for the treatment of CMD.
Silibinin Therapy Improves Cholangiocarcinoma Outcomes by Regulating ERK/Mitochondrial Pathway
Authors: Bai Yang , Chen Jiaqi , Hu Weijian , Wang Lei , Wu Yulian , Yu Shi’an
Published: March 2022

Background: Silibinin is widely utilized drug in various cancer treatments, though its application in cholangiocarcinoma has not yet been explored. For the first time, we evaluated the anticancer potential and underlying molecular mechanism of silibinin in treatment of cholangiocarcinoma treatment.

Methods: HuCCT-1 and CCLP-1 cells were chosen to be an in vitro study model and were exposed to various concentrations of silibinin for indicated times. Cell viability was evaluated by the cell counting kit-8 (CCK-8) assay and half maximal inhibitory (IC50) concentrations were calculated. Cell proliferation capacity was determined through the use of colony formation and 5-Ethynyl-2′- deoxyuridine (EdU) assays. Cell apoptosis and cycle arrest were assessed by Live/Dead staining assay and flow cytometry (FCM). The protein levels of extracellular regulated protein kinases (ERK)/mitochondrial apoptotic pathway were evaluated through western blotting (WB). Mitochondrial membrane potential changes were determined via 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1). A cholangiocarcinoma cell line xenograft model was used to assess the anti-tumor activity of silibinin in vivo.

Results: Inhibition of the ERK protein by silibinin led to a significant decrease in mitochondrial membrane potential, which, in turn, caused Cytochrome C to be released from the mitochondria. The activation of downstream apoptotic pathways led to apoptosis of cholangiocarcinoma cells. In general, silibinin inhibited the growth of cholangiocarcinoma cell line xenograft tumors.

Conclusions: Silibinin is able to inhibit cholangiocarcinoma through the ERK/mitochondrial apoptotic pathway, which makes silibinin a potential anti-tumor drug candidate for cholangiocarcinoma treatment.
Design of Plane Wave Generator Based on Strong Robust Inverse Radiation Problem Solving Method
Authors: HuYan Siteng , Chen Wei , Wang Shiquan , Du Liuge , Zhao Jia
Published: March 2022

In this manuscript, we reconsider the amplitude and phase combination of the plane-wave generator (PWG) from an electromagnetic field inverse radiation perspective and further propose a new method based on the Gauss-Newton inversion (GNI) to perform the inverse design of PWG. Furthermore, the wideband antenna pattern is applied in the transfer function and makes the inversion results closer to the engineering implementation. Compared with the traditional least-squares method (LSM) and singular value decomposition (SVD) method, the proposed method owns the merits of less amplitude range of the input source and stronger robustness.
The Potential for Outdoor Nature-Based Interventions in the Treatment and Prevention of Depression
Authors: Owens Matthew , Bunce Hannah L. I.
Published: March 2022

There is growing interest in nature-based interventions (NBI) to improve human health and wellbeing. An important nascent area is exploring the potential of outdoor therapies to treat and prevent common mental health problems like depression. In this conceptual analysis on the nature–depression nexus, we distil some of the main issues for consideration when NBIs for depression are being developed. We argue that understanding the mechanisms, or ‘active ingredients’ in NBIs is crucial to understand what works and for whom. Successfully identifying modifiable mediating intervention targets will pave the way for interventions with increased efficacy. We highlight a non-exhaustive list of five clinically relevant putative, candidate mechanisms which may underly the beneficial effects of NBIs on depression: stress, rumination, mindfulness, sleep and exercise. We also make the case that when developing NBIs it is important to not neglect young people, explore personalised approaches and focus on both treatment and prevention approaches. To achieve these aims methodologically rigorous programmes of clinical research are needed that include well-powered and controlled experimental designs including randomised controlled trials, qualitative research, longitudinal studies and large prospective cohorts.
Can Recurrent Neural Networks Validate Usage-Based Theories of Grammar Acquisition?
Authors: Pannitto Ludovica , Herbelot Aurelie
Published: March 2022

It has been shown that Recurrent Artificial Neural Networks automatically acquire some grammatical knowledge in the course of performing linguistic prediction tasks. The extent to which such networks can actually learn grammar is still an object of investigation. However, being mostly data-driven, they provide a natural testbed for usage-based theories of language acquisition. This mini-review gives an overview of the state of the field, focusing on the influence of the theoretical framework in the interpretation of results.
Assessing the Intention to Use Sports Bracelets Among Chinese University Students: An Extension of Technology Acceptance Model With Sports Motivation
Authors: Wang Yi , Zhang Xiaotian , Wang Li
Published: March 2022

The use of mobile technology, such as sports bracelets, is gaining popularity as it modifies the ways and processes of learning and teaching in college physical education (PE). However, little empirical evidence can be seen in literature to demonstrate crucial factors that influence university students’ acceptance of sports bracelets. Guided by the technology acceptance model (TAM), this study hence aimed at explaining university students’ intention to use sports bracelets. In total, 445 university students in China responded to a 19-item survey package. Results indicated that users’ attitudes toward technology and perceived usefulness were significant predictors of intention to use sports bracelets. Meanwhile, users’ intrinsic sports motivation significantly promoted users’ positive attitudes toward this technology and was significantly influenced by perceived ease of use and perceived usefulness. Overall, our findings highlighted the importance of stimulating young adults’ intrinsic sports motivation that facilitates their intention to use sports bracelets such that to develop a healthy lifestyle that benefits their physical health.
Decreased Transition Rate From Situational Insomnia to Chronic Insomnia by One-Week Internet Cognitive Behavioral Treatments for Insomnia During the COVID-19 Pandemic
Authors: Feng Fei , Zhang Chenxi , Liang Hanwen , Xu Guojian , Luo Xian , Liu Shuai , Xu Yan , Yang Lulu , Zhang Li , Lin Lianhong , Zhang Bin
Published: March 2022

Purpose

The purpose of the study was to determine the long-term effects of one-week self-guided internet cognitive behavioral treatments for insomnia (CBTI) on situational insomnia during the COVID-19 pandemic.

Patients and Methods

The participants with situational insomnia (n = 194) were recruited from March 2020 to April 2020 in Guangzhou, China. The insomnia severity index (ISI), pre-sleep arousal scale (PSAS), and hospital anxiety and depression scale (HADS) were evaluated at baseline and a one-week internet CBTI program was delivered to all individuals. The participants were divided into the complete treatment group (the participants completed all seven modules of the CBTI course, n = 75), and the incomplete treatment group (the participants completed 0–6 modules of the CBTI course, n = 119). A total of 135 participants completed the post-intervention assessments. At 3 months follow-up, a total of 117 participants (complete treatment group: n = 51; incomplete treatment group: n = 66) completed the assessments of the ISI, PSAS and HADS. The transition rate from situational insomnia to chronic insomnia (duration of insomnia ≥ 3 months and ISI ≥ 8) was calculated in the two groups. Linear mixed effect model was used to investigate the effect of group (between the two groups), time (baseline vs. follow-up), and interaction (group x time) on various questionnaire score.

Results

The transition rate from situational insomnia to chronic insomnia was significantly lower in the complete treatment group compared to the incomplete treatment group (27.5%, 14/51 vs. 48.5%, 32/66, p = 0.023). There were significant differences in group effect (p = 0.032), time effect (p = 0.000) and group × time effect (p = 0.048) between the two groups in the ISI total score. The ISI total scores decreased in both groups during follow-up compared to their baseline values, with a greater magnitude of decrease in the complete treatment group. There were no significant group x time effects between the two groups in the PSAS-total score, PSAS-somatic, PSAS-cognitive score, HADS total score, HADS anxiety score or HADS depression score.

Conclusion

Our results suggested that one-week self-guided internet CBTI prevented the development of chronic insomnia from situational insomnia during the COVID-19 pandemic.
Model Predictions of Occupational Exposures to Diacetyl and 2,3-Pentanedione Emitted From Roasted Whole Bean and Ground Coffee: Influence of Roast Level and Physical Form on Specific Emission Rates
Authors: LeBouf Ryan F. , Ranpara Anand , Fernandez Elizabeth , Burns Dru A. , Fortner Alyson R.
Published: March 2022

Roasted coffee emits hazardous volatile organic compounds including diacetyl and 2,3-pentanedione. Workers in non-flavored coffee roasting and packaging facilities might inhale diacetyl and 2,3-pentanedione from roasted coffee above occupational exposure limits depending on their work activities and proximity to the source of emissions. Objectives of this laboratory study were to: (1) investigate factors affecting specific emission rates (SERs) of diacetyl and 2,3-pentanedione from freshly roasted coffee, (2) explore the effect of time on SERs of coffee stored in sealed bags for 10-days, and (3) predict exposures to workers in hypothetical workplace scenarios. Two roast levels (light and dark) and three physical forms (whole bean, coarse ground, and fine ground) were investigated. Particle size for whole bean and ground coffee were analyzed using geometric mean of Feret diameter. Emitted chemicals were collected on thermal desorption tubes and quantified using mass spectrometry analysis. SERs developed here coupled with information from previous field surveys provided model input to estimate worker exposures during various activities using a probabilistic, near-field/far-field model. For freshly roasted coffee, mean SER of diacetyl and 2,3-pentantedione increased with decreasing particle size of the physical form (whole bean < coarse ground < fine ground) but was not consistent with roast levels. SERs from freshly roasted coffee increased with roast level for diacetyl but did not change for 2,3-pentanedione. Mean SERs were greatest for diacetyl at 3.60 mg kg−1 h−1 for dark, fine ground and for 2,3-pentanedione at 3.88 mg kg−1 h−1 for light, fine ground. For storage, SERs of whole bean remained constant while SERs of dark roast ground coffee decreased and light roast ground coffee increased. Modeling demonstrated that near-field exposures depend on proximity to the source, duration of exposure, and air velocities in the near-field further supporting previously reported chemical air measurements in coffee roasting and packaging facilities. Control of source emissions using local exhaust ventilation especially around grinding activities as well as modification of work practices could be used to reduce exposures in this workforce.
Non-Orthogonal Multiple Access: The Case of Improper Gaussian Signaling and Imperfect Successive Interference Cancellation
Authors: Abu Mahady Islam , Bedeer Ebrahim , Ikki Salama
Published: March 2022

This paper studies a two-user downlink non-orthogonal multiple access (NOMA) system that adopts an improper Gaussian signaling (IGS) strategy to compensate for the performance loss due to imperfect successive interference cancellation (SIC). Joint optimization problems are formulated to maximize the overall spectral efficiency and energy efficiency of a two-user NOMA system under minimum user-rate requirements and total power constraints. Sub-optimal solutions of IGS circularity coefficients and power allocation are obtained for the formulated problems. Furthermore, improper constellation diagrams are designed using widely linear transformation with predefined optimized IGS coefficients to study the impact of IGS on throughput and error performance. Simulation results show that the performance of IGS-based NOMA systems, where the IGS strategy is adopted by both users, outperforms that of the proper Gaussian signal (PGS)-based NOMA system under imperfect SIC.
The Load Structure in International Competitive Climbing
Authors: Winkler Marvin , Künzell Stefan , Augste Claudia
Published: March 2022

The analysis of the load structure in competitions is essential to develop performance structure models from which sport-specific testing and training protocols can be derived. The aim of this study was to characterize the external load structure of competitive climbing at an international level in the disciplines of speed, bouldering, lead, and Olympic combined based on video recordings of top athletes. In speed, the route was completed by women with a median of 11 moves and by men with 9 moves that required 0.73 and 0.60 s per move, respectively. Bouldering competitions are characterized by various bouts of activity with resting periods in between. Athletes attempted a boulder problem, a median of 3 times in the qualification and semi-final rounds and 4 times in the final round with an average attempt duration of 27.0 s. In lead, the load structure is characterized by an average climbing time of 4:09 min and 4:18 min, 31.6 and 30.0 actions, contact times of 6.4 s and 6.2 s, and reach times of 1.4 s and 1.6 s for women and men, respectively. Olympic combined competitions combine all 3 single disciplines starting with speed followed by bouldering and lead and are characterized by high competition loads, long durations of almost 3 h, and relatively short resting periods in between.
Hydrogen Peroxide Can Enhance the Synthesis of Bioactive Compounds in Harvested Broccoli Florets
Authors: Duarte-Sierra Arturo , Thomas Minty , Angers Paul , Arul Joseph
Published: March 2022

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) which participates in the signal transduction responses of plants toward biotic and abiotic stresses. Therefore, the objective of this study was to link the exposure of low doses of H2O2 to the improvement of the phytochemical composition of broccoli florets, in particular the content of glucosinolates (GLS), and hydroxy-cinnamates (HCA) without affecting the quality parameters of the vegetable. A dose of 1.25 mM H2O2 applied for 180 min was effective (hormetic) in maintaining the color of broccoli florets, which was also compared with a higher dose of 5.0 mM H2O2 applied for 180 min. The intensity of the treatments was related to respiration rate, which was monitored for 21 d at 4◦C along to weight loss. The initial respiration rate of florets exposed to both doses of H2O2 was significantly (p < 0.0001) higher relative to controls and resulted in weight loss in florets treated with the hormetic dose. The antioxidant capacity of florets, measured indirectly as Oxygen Radical Absorbance Capacity (ORAC) and ascorbic acid (AA), decreased in florets exposed to both doses. The concentration of glucobrassicins, aliphatic GLS, and HCA was consistently higher in florets treated with the two doses, compared to non-exposed florets. The enhancement of these compounds was accompanied by the over expression, immediately (6 h) after treatments, of tryptophan N-hydroxylase 2 (CYP79B3), dihomomethionine N-hydroxylase (CYP79F1), and phenylalanine ammonia-lyase (PAL) genes. Overall, the tested doses of H2O2 positively influenced the augmentation of indole-type and aliphatic GLS, as well as HCA in broccoli florets.
Population-Inclusive Assigned-Sex-at-Birth Estimation from Skull Computed Tomography Scans
Authors: Kelley Samantha R. , Tallman Sean D.
Published: March 2022

Methods for estimating assigned, binary sex at birth from skeletonized remains have primarily been developed for specific population groups in the U.S. (e.g., African American, European American, Hispanic) and, thus, inherently rely on ancestry estimation as a foundational component for constructing the biological profile. However, ongoing discussions in forensic anthropology highlight pressing issues with ancestry estimation practices. Therefore, this research provides population-inclusive assigned-sex estimation models for cases where ancestry is not estimated or is truly unknown. The study sample (n = 431) includes 3D volume-rendered skull computed tomography scans from the novel New Mexico Decedent Image Database of African, Asian, European, Latin, and Native Americans. Five standard nonmetric traits were scored, and eighteen standard measurements were obtained. Binary logistic regressions and discriminant function analyses were employed to produce models and classification accuracies, and intraobserver reliability was assessed. The population-inclusive nonmetric and metric models produced cross-validated classification accuracies of 81.0–87.0% and 86.7–87.0%, respectively, which did not differ significantly from the accuracy of most population-specific models. Moreover, combined nonmetric and metric models increased accuracy to 88.8–91.6%. This study indicates that population-inclusive assigned-sex estimation models can be used instead of population-specific models in cases where ancestry is intentionally not estimated, given current concerns with ancestry estimation.
Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
Authors: Lima Carla , Andrade-Barros Aline Ingrid , Bernardo Jefferson Thiago Gonçalves , Balogh Eniko , Quesniaux Valerie F. , Ryffel Bernhard , Lopes-Ferreira Monica
Published: March 2022

Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1β/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulting in self-DNA leaks into the cytosol, and whether the DNA sensor cGAS and STING pathway participate in triggering the innate immune response. Employing a peritonitis mouse model, we found that the deficiency of the tlr2/tlr4, myd88 and trif results in decreased neutrophil influx to peritoneal cavities of mice, indicative that in addition to MyD88, TRIF contributes to neutrophilia triggered by TLR4 engagement by Natterin. Next, we demonstrated that gpcr91 deficiency in mice abolished the neutrophil recruitment after Natterin injection, but mice pre-treated with 2-deoxy-d-glucose that blocks glycolysis presented similar infiltration than WT Natterin-injected mice. In addition, we observed that, compared with the WT Natterin-injected mice, DPI and cyclosporin A treated mice had a lower number of neutrophils in the peritoneal exudate. The levels of dsDNA in the supernatant of the peritoneal exudate and processed IL-33 in the supernatant of the peritoneal exudate or cytoplasmic supernatant of the peritoneal cell lysate of WT Natterin-injected mice were several folds higher than those of the control mice. The recruitment of neutrophils to peritoneal cavity 2 h post-Natterin injection was intensely impaired in ifnar KO mice and partially in il-28r KO mice, but not in ifnγr KO mice. Finally, using cgas KO, sting KO, or irf3 KO mice we found that recruitment of neutrophils to peritoneal cavities was virtually abolished in response to Natterin. These findings reveal cytosolic DNA sensors as critical regulators for Natterin-induced neutrophilia.
CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role
Authors: Tortora Fabiana , Rendina Antonella , Angiolillo Antonella , Di Costanzo Alfonso , Aniello Francesco , Donizetti Aldo , Febbraio Ferdinando , Vitale Emilia
Published: March 2022

The CD33 gene encodes for a member of the sialic-acid-binding immunoglobulin-type lectin (Siglec) family, and is one of the top-ranked Alzheimer’s disease (AD) risk genes identified by genome-wide association studies (GWAS). Many CD33 polymorphisms are associated with an increased risk of AD, but the function and potential mechanism of many CD33 single-nucleotide polymorphisms (SNPs) in promoting AD have yet to be elucidated. We recently identified the CD33 SNP rs2455069-A>G (R69G) in a familial form of dementia. Here, we demonstrate an association between the G allele of the rs2455069 gene variant and the presence of AD in a cohort of 195 patients from southern Italy. We carried out in silico analysis of the 3D structures of CD33 carrying the identified SNP to provide insights into its functional effect. Structural models of the CD33 variant carrying the R69G amino acid change were compared to the CD33 wild type, and used for the docking analysis using sialic acid as the ligand. Our analysis demonstrated that the CD33-R69G variant may bind sialic acid at additional binding sites compared to the wild type, thus potentially increasing its affinity/specificity for this molecule. Our results led to a new hypothesis of rs2455069-A>G SNP as a risk factor for AD, suggesting that a long-term cumulative effect of the CD33-R69G variant results from the binding of sialic acid, acting as an enhancer of the CD33 inhibitory effects on amyloid plaque degradation.
Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression
Authors: Li Lingfei , Ho Philip Wing-Lok , Liu Huifang , Pang Shirley Yin-Yu , Chang Eunice Eun-Seo , Choi Zoe Yuen-Kiu , Malki Yasine , Kung Michelle Hiu-Wai , Ramsden David Boyer , Ho Shu-Leong
Published: March 2022

Synaptogyrin-3 (SYNGR3) is a synaptic vesicular membrane protein. Amongst four homologues (SYNGR1 to 4), SYNGR1 and 3 are especially abundant in the brain. SYNGR3 interacts with the dopamine transporter (DAT) to facilitate dopamine (DA) uptake and synaptic DA turnover in dopaminergic transmission. Perturbed SYNGR3 expression is observed in Parkinson’s disease (PD). The regulatory elements which affect SYNGR3 expression are unknown. Nuclear-receptor-related-1 protein (NURR1) can regulate dopaminergic neuronal differentiation and maintenance via binding to NGFI-B response elements (NBRE). We explored whether NURR1 can regulate SYNGR3 expression using an in silico analysis of the 5′-flanking region of the human SYNGR3 gene, reporter gene activity and an electrophoretic mobility shift assay (EMSA) of potential cis-acting sites. In silico analysis of two genomic DNA segments (1870 bp 5′-flanking region and 1870 + 159 bp of first exon) revealed one X Core Promoter Element 1 (XCPE1), two SP1, and three potential non-canonical NBRE response elements (ncNBRE) but no CAAT or TATA box. The longer segment exhibited gene promoter activity in luciferase reporter assays. Site-directed mutagenesis of XCPE1 decreased promoter activity in human neuroblastoma SH-SY5Y (↓43.2%) and human embryonic kidney HEK293 cells (↓39.7%). EMSA demonstrated NURR1 binding to these three ncNBRE. Site-directed mutagenesis of these ncNBRE reduced promoter activity by 11–17% in SH-SY5Y (neuronal) but not in HEK293 (non-neuronal) cells. C-DIM12 (Nurr1 activator) increased SYNGR3 protein expression in SH-SY5Y cells and its promoter activity using a real-time luciferase assay. As perturbed vesicular function is a feature of major neurodegenerative diseases, inducing SYNGR3 expression by NURR1 activators may be a potential therapeutic target to attenuate synaptic dysfunction in PD.
Acute Kidney Injury and Gut Dysbiosis: A Narrative Review Focus on Pathophysiology and Treatment
Authors: Chou Yu-Ting , Kan Wei-Chih , Shiao Chih-Chung
Published: March 2022

Acute kidney injury (AKI) and gut dysbiosis affect each other bidirectionally. AKI induces microbiota alteration in the gastrointestinal (GI) system, while gut dysbiosis also aggravates AKI. The interplay between AKI and gut dysbiosis is not yet well clarified but worthy of further investigation. The current review focuses on the pathophysiology of this bidirectional interplay and AKI treatment in this base. Both macrophages and neutrophils of the innate immunity and the T helper type 17 cell from the adaptive immunity are the critical players of AKI-induced gut dysbiosis. Conversely, dysbiosis-induced overproduction of gut-derived uremic toxins and insufficient generation of short-chain fatty acids are the main factors deteriorating AKI. Many novel treatments are proposed to deter AKI progression by reforming the GI microbiome and breaking this vicious cycle. Data support the benefits of probiotic treatment in AKI patients, while the results of postbiotics are mainly limited to animals. Prebiotics and synbiotics are primarily discussed in chronic kidney disease patients rather than AKI patients. The effect of adsorbent treatment seems promising, but more studies are required before the treatment can be applied to patients. Immune therapy and some repurposed drugs such as allopurinol are prospects of future treatments and are worth more discussion and survey.
Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer
Authors: Shi Jingwei , Shen Xiao , Kang Qi , Yang Xing , Denzinger Maximilian , Kornmann Marko , Traub Benno
Published: March 2022

In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.
Probing Photoreceptor Outer Segment Phagocytosis by the RPE In Vivo: Models and Methodologies
Authors: Vargas Jade A. , Finnemann Silvia C.
Published: March 2022

In the vertebrate retina, the light-sensitive photoreceptor rods and cones constantly undergo renewal by generating new portions of the outer segment and shedding their distal, spent tips. The neighboring RPE provides the critical function of engulfing the spent material by phagocytosis. RPE phagocytosis of shed rod outer segment fragments is a circadian process that occurs in a burst of activity shortly after daily light onset with low activity at other times, a rhythm that has been reported for many species and over 50 years. In this review, we compare studies on the rhythm and quantity of RPE phagocytosis using different in vivo model systems and assessment methods. We discuss how measurement methodology impacts the observation and analysis of RPE phagocytosis. Published studies on RPE phagocytosis investigating mice further suggest that differences in genetic background and housing conditions may affect results. Altogether, a comparison between RPE phagocytosis studies performed using differing methodology and strains of the same species is not as straightforward as previously thought.
Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
Authors: Cartee Naw May Pearl , Lee Soo Jung , Young Kelly Z. , Zhang Xiaojie , Wang Michael M.
Published: March 2022

Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states as potential triggers of cerebral vascular smooth muscle cytopathology. In this report, we describe a novel property of the second EGF-like domain of NOTCH3: its capacity to alter the cysteine redox state of the NOTCH3 ectodomain. Synthetic peptides corresponding to this sequence (NOTCH3 N-terminal fragment 2, NTF2) readily reduce NOTCH3 N-terminal ectodomain polypeptides in a dose- and time-dependent fashion. Furthermore, NTF2 preferentially reduces regional domains of NOTCH3 with the highest intensity against EGF-like domains 12–15. This process requires cysteine residues of NTF2 and is also capable of targeting selected extracellular proteins that include TSP2 and CTSH. CADASIL mutations in NOTCH3 increase susceptibility to NTF2-facilitated reduction and to trans-reduction by NOTCH3 produced in cells. Moreover, NTF2 forms complexes with the NOTCH3 ectodomain, and cleaved NOTCH3 co-localizes with the NOTCH3 ectodomain in cerebral arteries of CADASIL patients. The potential for NTF2 to reduce vascular proteins and the enhanced preference for it to trans-reduce mutant NOTCH3 implicate a role for protein trans-reduction in cerebrovascular pathological states such as CADASIL.
Cell-Based Chemical Safety Assessment and Therapeutic Discovery Using Array-Based Sensors
Authors: Jiang Mingdi , Chattopadhyay Aritra Nath , Rotello Vincent M.
Published: March 2022

Synthetic chemicals are widely used in food, agriculture, and medicine, making chemical safety assessments necessary for environmental exposure. In addition, the rapid determination of chemical drug efficacy and safety is a key step in therapeutic discoveries. Cell-based screening methods are non-invasive as compared with animal studies. Cellular phenotypic changes can also provide more sensitive indicators of chemical effects than conventional cell viability. Array-based cell sensors can be engineered to maximize sensitivity to changes in cell phenotypes, lowering the threshold for detecting cellular responses under external stimuli. Overall, array-based sensing can provide a robust strategy for both cell-based chemical risk assessments and therapeutics discovery.
Analysis of microRNAs in Exosomes of Breast Cancer Patients in Search of Molecular Prognostic Factors in Brain Metastases
Authors: Curtaz Carolin J. , Reifschläger Leonie , Strähle Linus , Feldheim Jonas , Feldheim Julia J. , Schmitt Constanze , Kiesel Matthias , Herbert Saskia-Laureen , Wöckel Achim , Meybohm Patrick , Burek Malgorzata
Published: March 2022

Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use.
Novel Device Used to Monitor Hand Tremors during Nocturnal Hypoglycemic Events
Authors: Al-Aboosi Abdullah F. , Fink Rainer
Published: March 2022

Diabetes is one of the lifelong diseases that require systematic medical care to avoid life-menacing ramifications. Uncontrolled diabetes can cause severe damage to most internal body organs, probably leading to death. Particularly, nocturnal hypoglycemic that occur usually at night during sleep. Severe cases of these events can lead to seizures, fainting, loss of consciousness, and death. The current medical devices lack to give the warning to reduce the risk of acquiring nocturnal hypoglycemic events because they use only for glucose monitoring during waking times. Consequently, the main goal of this work is to design and implement a new wearable device to detect and monitor tremors, which occur when a user has hypoglycemia (low blood sugar). The device can detect a frequency range of 4–12 Hz by using the accelerometer of Arduino Nano 33 BLE. It can send a signal to the phone application (app) via Bluetooth Low Energy (BLE). Once the phone receives a signal, the phone application can activate an alarm system to wake up the patient, call three selected contacts number, and universal emergency number. In case of the user is unresponsive, the app can provide the patient’s location, name, and date of birth to the emergency contacts numbers and universal emergency number. Additionally, the device cost is economically feasible and competitive compared to other medical devices.
Agricultural Development in the Fight against Poverty: The Case of South Kivu, DR Congo
Authors: Angélique Neema Ciza , Stany Vwima , Lebailly Philippe , Azadi Hossein
Published: March 2022

Agriculture plays a prominent role in the economy of the Democratic Republic of Congo (DRC) and has considerable production potential. One of the most populous and poorest provinces in DRC is South Kivu, where many people live below the poverty line. This paper aimed to understand agricultural development’s role in reducing poverty and maintaining rural households’ food security in the DRC. This study developed a questionnaire to evaluate the household identity, source of income, access to land, crops grown on the land, farming and animal husbandry practices, and constraints faced by households in relation to agriculture. The survey included meetings with farm heads, data collection from 120 households on household characteristics of their livelihoods (human capital, land capital, social capital, financial, etc.), as well as an overview of living conditions and income from agricultural activities. The data were processed and analyzed using R 3.6.2 and Excel software. The results showed that access to land is problematic with relatively small farms, especially when one considers that household size is high and therefore, the “area per farm” ratio is low. Moreover, agriculture generates very little income and it is therefore very difficult for a farmer to emerge from poverty. As a result, implementing an effective and equitable anti-poverty policy in rural areas is important to address the issue of farming household incomes and target low incomes from all sources of income.
Synthesis and Characterization of LaNi0.5Ti0.5O3 and La2NiTiO6 Double Perovskite Nanoparticles
Authors: Córdova-Calderón José , Tuza Pablo V. , Souza Mariana M. V. M.
Published: March 2022

In the present work, LaNi0.5Ti0.5O3 and La2NiTiO6 nanoparticles were synthesized by the modified Pechini method. LaNi0.5Ti0.5O3 was calcined at 1073 K for 17 h or 100 h, while La2NiTiO6 was calcined at 1273 K for 135 h. The double perovskite calcined at 1073 K for 17 h presented orthorhombic symmetry with Pbnm space group, mean particle size was 31.9 ± 1 nm, random ordering of Ni2+ and Ti4+ cations, Néel temperature close to 15 K, and magnetic moment of 1.29 μB. By increasing the calcination time, this material showed the same symmetry and space group, a mean particle size of 50.7 ± 2 nm, short-range ordering of Ni2+ and Ti4+ cations, Néel temperature around 12 K, and magnetic moment of 0.96 μB. La2NiTiO6 presented a monoclinic crystal structure, with P21/n space group, mean particle size of 80.0 ± 5 nm, rock salt ordering of Ni2+ and Ti4+, Néel temperature of approximately 23 K, and magnetic moment of 2.75 μB.