bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Affecting the Delivery and Acceptability of the ROWTATE Telehealth Vocational Rehabilitation Intervention for Traumatic Injury Survivors: A Mixed-Methods Study
Authors: Kettlewell Jade , Lindley Rebecca , Radford Kate , Patel Priya , Bridger Kay , Kellezi Blerina , Timmons Stephen , Andrews Isabel , Fallon Stephen , Lannin Natasha , Holmes Jain , Kendrick Denise , Team on
Published: September 2021

Background: Returning to work after traumatic injury can be problematic. We developed a vocational telerehabilitation (VR) intervention for trauma survivors, delivered by trained occupational therapists (OTs) and clinical psychologists (CPs), and explored factors affecting delivery and acceptability in a feasibility study. Methods: Surveys pre- (5 OTs, 2 CPs) and post-training (3 OTs, 1 CP); interviews pre- (5 OTs, 2 CPs) and post-intervention (4 trauma survivors, 4 OTs, 2 CPs). Mean survey scores for 14 theoretical domains identified telerehabilitation barriers (score ≤ 3.5) and facilitators (score ≥ 5). Interviews were transcribed and thematically analysed. Results: Surveys: pre-training, the only barrier was therapists’ intentions to use telerehabilitation (mean = 3.40 ± 0.23), post-training, 13/14 domains were facilitators. Interviews: barriers/facilitators included environmental context/resources (e.g., technology, patient engagement, privacy/disruptions, travel and access); beliefs about capabilities (e.g., building rapport, complex assessments, knowledge/confidence, third-party feedback and communication style); optimism (e.g., impossible assessments, novel working methods, perceived importance and patient/therapist reluctance) and social/professional role/identity (e.g., therapeutic methods). Training and experience of intervention delivery addressed some barriers and increased facilitators. The intervention was acceptable to trauma survivors and therapists. Conclusion: Despite training and experience in intervention delivery, some barriers remained. Providing some face-to-face delivery where necessary may address certain barriers, but strategies are required to address other barriers.
Postcoital Vaginal Perforation and Evisceration in Women with No Prior Pelvic Surgery: Laparoscopic Management and Systematic Review of the Literature
Authors: Stabile Guglielmo , Mordeglia Denise , Romano Federico , Carlucci Stefania , Mangino Francesco Paolo , Nappi Luigi , Sorrentino Felice , De Manzini Nicolò , Ricci Giuseppe
Published: September 2021

Objective: to evaluate risk factors, causes, management and surgical therapy of postcoital vaginal perforation and evisceration in women with no prior pelvic surgery. Data sources: We used MEDLINE (PubMed), Scopus, Embase and Web of Science for our research. Our review includes all reports from 1980 to November 2020. The research strategy adopted included different combinations of the following terms: (intercourse) AND (coitus) AND (vaginal perforation). Methods of study selection: we report a case of vaginal evisceration after consensual intercourse in a young and healthy woman. In addition, we performed a systematic review of vaginal perforations with or without evisceration in women without prior surgery or any other predisposing disease. All studies identified were listed by citation, title, authors and abstract. Duplicates were identified by an independent manual screening, performed by one researcher and then removed. For the eligibility process, two authors independently screened the title and abstracts of all non-duplicated papers and excluded those not pertinent to the topic. Tabulation, integration and results: We have followed the PRISMA guidelines. Five manuscripts were detected through the references of the works that had been identified with the research on MEDLINE (PubMed), Scopus, Embase and Web of Science. We found 16 cases between 1980 and 2020. The young age and the virginal status represent the principal risk factors and all the lacerations occurred in the posterior vaginal fornix. The most common surgical technique was the laparotomic approach and, in the remaining cases, the laparoscopic and vaginal route was performed. Conclusions: Post-coital vaginal perforation and evisceration in women with no prior pelvic surgery is a rare condition in the clinical practice and, when it is associated with evisceration it is a surgical emergency. Usually, these injuries are not life-threatening conditions but, a delay in diagnosis, can lead to severe complications. In consideration of the high heterogeneity of the data in the literature, it is essential to define a diagnostic–therapeutic management for the patients with vaginal perforation. With our review, we try to identify the associated risk factors, the best and fastest diagnosis, and the best surgical approach. We believe that a combined vaginal and laparoscopic approach can be the best surgical treatment, useful to diagnose injuries of the abdominal organs and to improve postoperative outcome.
Impact of Inpatient Unit Design Features on Overall Patient Experience and Perceived Room-Level Call Button Response
Authors: Cai Hui , Fullam Francis , MacAllister Lorissa , Fogg Louis F. , Canar Jeff , Press Irwin , Weissman Connie , Velasquez Olivia
Published: September 2021

This study explores the relationship between inpatient unit design and patient experience and how spatial features and visibility impact patients’ perception of staff responsiveness. The first part of this study is a retrospective pre–post and cross-sectional study evaluating the impacts of unit design on patient experience at the unit level. This study compares patient experiences based on Press Ganey and HCAHPS surveys in two orthopedic units (existing unit in Atrium building and new unit in Tower) with differing design features at Rush University Medical Center. The chi-square test results show that when moving from the old orthopedic unit to the new unit, almost all patient survey items related to patient experience showed statistically significant improvements. The second part of this study is a room level on the new unit. The ANOVA and Pearson correlation tests revealed that the visibility measure of metric step depth had significant impacts on patients’ perception of staff’s “promptness in responding to call button” and “help with toileting”. This study confirms that inpatient unit design plays a direct role in improvement for patient experience and should be considered as an important area of focus for future development.
Cardiorespiratory Interaction and Autonomic Sleep Quality Improve during Sleep in Beds Made from Pinus cembra (Stone Pine) Solid Wood
Authors: Grote Vincent , Frühwirth Matthias , Lackner Helmut K. , Goswami Nandu , Köstenberger Markus , Likar Rudolf , Moser Maximilian
Published: September 2021

Cardiorespiratory interactions (CRIs) reflect the mutual tuning of two important organismic oscillators—the heartbeat and respiration. These interactions can be used as a powerful tool to characterize the self-organizational and recreational quality of sleep. In this randomized, blinded and cross-over design study, we investigated CRIs in 15 subjects over a total of 253 nights who slept in beds made from different materials. One type of bed, used as control, was made of melamine faced chipboard with a wood-like appearance, while the other type was made of solid wood from stone pine (Pinus cembra). We observed a significant increase of vagal activity (measured by respiratory sinus arrhythmia), a decrease in the heart rate (as an indicator of energy consumption during sleep) and an improvement in CRIs, especially during the first hours of sleep in the stone pine beds as compared to the chipboard beds. Subjective assessments of study participants’ well-being in the morning and sub-scalar assessments of their intrapsychic stability were significantly better after they slept in the stone pine bed than after they slept in the chipboard bed. Our observations suggest that CRIs are sensitive to detectable differences in indoor settings that are relevant to human health. Our results are in agreement with those of other studies that have reported that exposure to volatile phytochemical ingredients of stone pine (α-pinene, limonene, bornyl acetate) lead to an improvement in vagal activity and studies that show a reduction in stress parameters upon contact with solid wood surfaces.
Effects of Montmorency Tart Cherry and Blueberry Juice on Cardiometabolic Outcomes in Healthy Individuals: Protocol for a 3-Arm Placebo Randomized Controlled Trial
Authors: Sinclair Jonathan , Shadwell Gareth , Dillon Stephanie , Allan Robert , Butters Bobbie , Bottoms Lindsay
Published: September 2021

Cardiometabolic disease is recognized as the predominant cause of global mortality and healthcare expenditure. Whilst pharmaceutical interventions are effective in the short term, their long-term efficacy remain equivocal and their associated side-effects are concerning. Owing to their high levels of anthocyanins, Montmorency tart cherries and blueberries have been cited as potentially important natural treatment/preventative modalities for cardiometabolic disease. This study proposed a randomized controlled trial, aims to test the effects of consumption of Montmorency tart cherry and blueberry juice on cardiometabolic outcomes compared to placebo. This 20-day, parallel, single-blind, randomized, placebo-controlled trial will recruit 45 individuals, who will be assigned to receive 60 mL per day of either Montmorency tart cherry juice, blueberry juice or a cherry/blueberry flavoured placebo. The primary study outcome is the between-group difference in systolic blood pressure from baseline to post-intervention. Secondary outcome measures will be between-group differences in anthropometric, energy expenditure and substrate oxidation (during rest and physical activity), haematological, blood pressure/resting heart rate, psychological wellbeing and sleep efficacy indices. Statistical analysis will be conducted on an intention-to-treat basis. This study has been granted ethical approval by the University of Central Lancashire, Health Research Ethics Committee (ref: HEALTH 0016) and formally registered as a trial. Dissemination of the study findings from this investigation will be through publication in a leading peer-reviewed journal.
A Path Model for Burnout in Community Mental Health Professionals
Authors: Chang Jin-Joo , Shin Sung-Hee
Published: September 2021

The purpose of this research is to identify a path model to explain burnout in community mental health professionals based on the compassion satisfaction–compassion fatigue (CS-CF) model. A total of 125 mental health professionals, including nurses, social professionals, and psychologists working in mental health welfare centers in various regions across South Korea were surveyed using a structured questionnaire. A path analysis was conducted using SPSS 24.0 and AMOS 24.0. The results showed that compassion satisfaction and compassion fatigue are significant predictors of burnout (β = −0.20, p = 0.011; β = 0.40, p < 0.001, respectively). The indirect pathways associated with burnout included occupational stress (β = 0.21, p = 0.021) and experience with aggressive behavior in the workplace (β = 0.33, p = 0.004) through maladaptive cognitive emotion regulation and compassion satisfaction. The total effect of the variables on burnout via compassion fatigue and compassion satisfaction explained 62.5% of burnout among mental health professionals. These findings indicate that providing nursing interventions might reduce compassion fatigue and increase compassion satisfaction to reduce burnout. Furthermore, intervention programs that help to reduce the use of maladaptive cognitive emotion regulation strategies are necessary to effectively reduce burnout in mental health professionals.
The Importance of Close Follow-Up in Patients with Early-Grade Diabetic Retinopathy: A Taiwan Population-Based Study Grading via Deep Learning Model
Authors: Lee Chia-Cheng , Hsing Shi-Chue , Lin Yu-Ting , Lin Chin , Chen Jiann-Torng , Chen Yi-Hao , Fang Wen-Hui
Published: September 2021

(1) Background: Diabetic retinopathy (DR) can cause blindness. Current guidelines on diabetic eye care recommend more frequent eye examinations for more severe DR to prevent deterioration. However, close follow-up and early intervention at earlier stages are important for the prevention of disease progression of other diabetes mellitus (DM) complications. The study was designed to investigate the association between different stages of DR in type 2 DM patients and the progression of DR; (2) Methods: A total of 2623 type 2 DM patients were included in this study. In these patients, a total of 14,409 fundus color photographs was obtained. The primary outcome was the progression of DR; (3) Results: The progression of DR was highly associated with the initial grade of DR (p < 0.001). Severe nonproliferative diabetic retinopathy (NPDR) was the most likely to progress to proliferative diabetic retinopathy (PDR), followed by moderate NPDR, mild NPDR, and no retinopathy. However, progression to the next stage of DR showed a different trend. We used no retinopathy as a reference. Mild NPDR showed the highest risk for progression to the next stage [hazard ratio (HR): 2.00 (95% conference interval (CI): 1.72–2.32)] relative to higher initial grades [HR (moderate NPDR): 1.82 (95% CI: 1.58–2.09) and HR (severe NPDR): 0.87 (95% CI: 0.69–1.09)]. The same trend was observed in the multivariate analysis, in which mild NPDR presented the highest risk for progression to the next stage (adjusted HR (mild NPDR): 1.95 (95% CI: 1.68–2.27), adjusted HR (moderate NPDR): 1.73 (95% CI: 1.50–1.99), and adjusted HR (severe NPDR): 0.82 (95% CI: 0.65–1.03)); (4) Conclusions: Type 2 diabetic patients with earlier-grade DR appeared to exhibit more rapid development to the next grade in our study. As these findings show, more frequent fundus color photography follow-up in earlier-grade DR patients is important to slow DR progression and awaken self-perception.
Association between Chronic Knee Pain and Psychological Stress in Those over 50 Years of Age: A Nationwide Cross-Sectional Study Based on the Sixth Korea National Health and Nutrition Examination Survey (KNHANES 2013–2015)
Authors: Nah Sangun , Park Seong-San , Choi Sungwoo , Jang Hae-Dong , Moon Ji-Eun , Han Sangsoo
Published: September 2021

Chronic knee pain (CKP) can degrade the quality of life and cause dysfunction, resulting in the loss of independence. Psychological stress not only affects physical and mental health but is also a risk factor for CKP. In this cross-sectional study, we analyzed data from the sixth Korea National Health and Nutrition Examination Survey (2013–2015), and investigated the association between CKP and psychological stress of the Korean general population. The CKP status was determined based on survey responses of self-reported knee pain lasting for more than 30 days during the last 3 months. Psychological stress was classified as none, mild, moderate, or severe. The association between CKP and psychological stress was analyzed using multiple logistic regression analysis considering co-variables and demographic data. Logistic regression analysis adjusting for co-variables indicated that the risk of CKP increased with an increasing degree of stress, from mild (OR = 1.65, 95% CI 1.35–2.03, p < 0.001) to moderate (OR = 2.00, 95% CI 1.56–2.57, p < 0.001) and severe (OR = 3.02, 95% CI 2.08–4.37, p < 0.001). A significant association between the risk of CKP and psychological stress was identified. Therefore, when evaluating patients with CKP, it may be helpful for clinicians to check the degree of stress.
Combined Effects of Different Endocrine-Disrupting Chemicals (EDCs) on Prostate Gland
Authors: De Falco Maria , Laforgia Vincenza
Published: September 2021

Endocrine-disrupting chemicals (EDCs) belong to a heterogeneous class of environmental pollutants widely diffused in different aquatic and terrestrial habitats. This implies that humans and animals are continuously exposed to EDCs from different matrices and sources. Moreover, pollution derived from anthropic and industrial activities leads to combined exposure to substances with multiple mechanisms of action on the endocrine system and correlated cell and tissue targets. For this reason, specific organs, such as the prostate gland, which physiologically are under the control of hormones like androgens and estrogens, are particularly sensitive to EDC stimulation. It is now well known that an imbalance in hormonal regulation can cause the onset of various prostate diseases, from benign prostate hyperplasia to prostate cancer. In this review, starting with the description of normal prostate gland anatomy and embryology, we summarize recent studies reporting on how the multiple and simultaneous exposure to estrogenic and anti-androgenic compounds belonging to EDCs are responsible for an increase in prostate disease incidence in the human population.
The Impact of Peer Attachment on Left-Behind Children’s Pathological Internet Use: A Moderated Mediating Effect Model
Authors: Zhang Demei , Wang Shutao
Published: September 2021

The aim of this study was to determine how left-behind children’s perceived personal rejection and emotional intelligence impact on the relationship between their peer attachment and pathological Internet use in China. Using the cluster random sampling method, a total of 406 left-behind children (aging 12.76 ± 2.13) from six rural primary and secondary schools in mainland China were recruited for the study (202 males and 204 females). The results of the analysis indicated that peer attachment negatively predicted left-behind children’s pathological Internet use. Perceived personal rejection had a mediating effect on the relationship between peer attachment and pathological Internet use, whereas emotional intelligence had a moderating effect on the relationships between peer attachment and perceived personal rejection and between peer attachment and pathological Internet use among these children. Moreover, peer attachment had a greater negative impact on the perceived personal rejection and pathological Internet use of left-behind children with high emotional intelligence compared with those of students with low emotional intelligence. These findings reveal the need for more support and interventions aimed at strengthening peer attachment and emotional intelligence of left-behind primary and secondary children and reducing their perceptions of personal rejection, which, in turn, reduces their pathological Internet use.
The Particularities of Pharmaceutical Care in Improving Public Health Service during the COVID-19 Pandemic
Authors: Ghibu Steliana , Juncan Anca Maria , Rus Luca Liviu , Frum Adina , Dobrea Carmen Maximiliana , Chiş Adriana Aurelia , Gligor Felicia Gabriela , Morgovan Claudiu
Published: September 2021

Nowadays, humanity is confronted with one of the most difficult challenges. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified for the first time in Hubei, China in December 2019 and produced the COVID-19 pandemic, a devastating disease that led to many complications and deaths. The authorities and the global healthcare system have been alerted regarding the prevention and treatment of this pathology. Even though worldwide quarantine was declared, health care professionals, including pharmacists, have been at the frontline in this war. Since the beginning of the pandemic, the authorities relied on the involvement of the community, hospital, or clinical pharmacists in offering support to the entire population. Also, the authorities implemented measures for emergency authorization of the vaccines, or the drugs used in COVID-19 treatment. In order to facilitate the population’s access to healthcare services, the authorities have established regulations regarding, the extension of prescriptions by pharmacists, working hours, prevention of shortages and price-increase, drive-thru services, etc. However, several countries have taken financial measures to support the pharmacies’ activity. At the same time, pharmaceutical associations elaborated guidelines for the protection of pharmacists and patients alike. Additionally, the pharmacies have come to support the health system and patients by adapting pharmaceutical care to the new needs like preparation and supply of disinfectants, patient care, information, and counseling, especially to COVID-19 patients, as well as the implementation of home drugs-delivery systems. The important roles played by pharmacists were to perform COVID-19 tests and further vaccines, as well as to combat the abundance of misinformation and fake news. The clinical and hospital pharmacy services have also been adapted. Strengthening the role of the pharmacist in the medical team was important for the purpose of providing correct and complete information regarding drugs used in the COVID-19 pathology. In all these activities, pharmacists needed creativity and professionalism, but also the support of pharmacy owners and managers. With this crisis, pharmaceutical care has entered a new phase, demonstrating the ability of pharmacists to be competent and accessible providers of public health. Based on this information, we conducted a narrative review whose purpose was to identify the impact of the authorities’ decisions on pharmaceutical practice, the involvement of professional associations, and the responsibilities of the pharmacy owners and management. On the other hand, we performed a global assessment on the pharmaceutical care services provided by community pharmacists as well as by clinical or hospital pharmacists during the COVID-19 pandemic.
Modeling and Processing of Smart Point Clouds of Cultural Relics with Complex Geometries
Authors: Yang Su , Hou Miaole , Shaker Ahmed , Li Songnian
Published: September 2021

The digital documentation of cultural relics plays an important role in archiving, protection, and management. In the field of cultural heritage, three-dimensional (3D) point cloud data is effective at expressing complex geometric structures and geometric details on the surface of cultural relics, but lacks semantic information. To elaborate the geometric information of cultural relics and add meaningful semantic information, we propose a modeling and processing method of smart point clouds of cultural relics with complex geometries. An information modeling framework for complex geometric cultural relics was designed based on the concept of smart point clouds, in which 3D point cloud data are organized through the time dimension and different spatial scales indicating different geometric details. The proposed model allows smart point clouds or a subset to be linked with semantic information or related documents. As such, this novel information modeling framework can be used to describe rich semantic information and high-level details of geometry. The proposed information model not only expresses the complex geometric structure of the cultural relics and the geometric details on the surface, but also has rich semantic information, and can even be associated with documents. A case study of the Dazu Thousand-Hand Bodhisattva Statue, which is characterized by a variety of complex geometries, reveals that our proposed framework is capable of modeling and processing the statue with excellent applicability and expansibility. This work provides insights into the sustainable development of cultural heritage protection globally.
Autonomous Obstacle Avoidance Algorithm for Unmanned Surface Vehicles Based on an Improved Velocity Obstacle Method
Authors: Ren Jia , Zhang Jing , Cui Yani
Published: September 2021

Focusing on the collision avoidance problem for Unmanned Surface Vehicles (USVs) in the scenario of multi-vessel encounters, a USV autonomous obstacle avoidance algorithm based on the improved velocity obstacle method is proposed. The algorithm is composed of two parts: a multi-vessel encounter collision detection model and a path re-planning algorithm. The multi-vessel encounter collision detection model draws on the idea of the velocity obstacle method through the integration of characteristics such as the USV dynamic model in the marine environment, the encountering vessel motion model, and the International Regulations for Preventing Collisions at Sea (COLREGS) to obtain the velocity obstacle region in the scenario of USV and multi-vessel encounters. On this basis, two constraint conditions for the motion state space of USV obstacle avoidance behavior and the velocity obstacle region are added to the dynamic window algorithm to complete a USV collision risk assessment and generate a collision avoidance strategy set. The path re-planning algorithm is based on the premise of the minimum resource cost and uses an improved particle swarm algorithm to obtain the optimal USV control strategy in the collision avoidance strategy set and complete USV path re-planning. Simulation results show that the algorithm can enable USVs to safely evade multiple short-range dynamic targets under COLREGS.
Production of a Potentially Probiotic Product for Animal Feed and Evaluation of Some of Its Probiotic Properties
Authors: Agregán-Pérez Rubén , Alonso-González Elisa , Mejuto Juan Carlos , Pérez-Guerra Nelson
Published: September 2021

Nowadays, probiotics have been proposed for substituting antibiotics in animal feed since the European Union banned the latter compounds in 2006 to avoid serious side effects on human health. Therefore, this work aimed to produce a probiotic product for use in animal feed by fed-batch fermentation of whey with a combination of kefir grains, AGK1, and the fermented whole milk used to activate these kefir grains. The probiotic culture obtained was characterized by high levels of biomass (8.03 g/L), total viability (3.6 × 108 CFU/mL) and antibacterial activity (28.26 Activity Units/mL). Some probiotic properties of the probiotic culture were investigated in vitro, including its survival at low pH values, under simulated gastrointestinal conditions, after freezing in skim milk at −20 °C, and in the commercial feed during storage at room temperature. The viable cells of lactic and acetic acid bacteria and yeasts exhibited higher tolerance to acidic pH and simulated gastrointestinal conditions when the cells were protected with skim milk and piglet feed, compared with washed cells. The results indicated the feasibility of producing a probiotic product at a low cost with a potential application in animal feed.
Vitamin D and Platelets: A Menacing Duo in COVID-19 and Potential Relation to Bone Remodeling
Authors: Salamanna Francesca , Maglio Melania , Sartori Maria , Landini Maria Paola , Fini Milena
Published: September 2021

Global data correlate severe vitamin D deficiency with COVID-19-associated coagulopathy, further suggesting the presence of a hypercoagulable state in severe COVID-19 patients, which could promote thrombosis in the lungs and in other organs. The feedback loop between COVID-19-associated coagulopathy and vitamin D also involves platelets (PLTs), since vitamin D deficiency stimulates PLT activation and aggregation and increases fibrinolysis and thrombosis. Vitamin D and PLTs share and play specific roles not only in coagulation and thrombosis but also during inflammation, endothelial dysfunction, and immune response. Additionally, another ‘fil rouge’ between vitamin D and PLTs is represented by their role in mineral metabolism and bone health, since vitamin D deficiency, low PLT count, and altered PLT-related parameters are linked to abnormal bone remodeling in certain pathological conditions, such as osteoporosis (OP). Hence, it is possible to speculate that severe COVID-19 patients are characterized by the presence of several predisposing factors to bone fragility and OP that may be monitored to avoid potential complications. Here, we hypothesize different pervasive actions of vitamin D and PLT association in COVID-19, also allowing for potential preliminary information on bone health status during COVID-19 infection.
Key Physicochemical Determinants in the Antimicrobial Peptide RiLK1 Promote Amphipathic Structures
Authors: Falcigno Lucia , D’Auria Gabriella , Palmieri Gianna , Gogliettino Marta , Agrillo Bruna , Tatè Rosarita , Dardano Principia , Nicolais Luigi , Balestrieri Marco
Published: September 2021

Antimicrobial peptides (AMPs) represent a skilled class of new antibiotics, due to their broad range of activity, rapid killing, and low bacterial resistance. Many efforts have been made to discover AMPs with improved performances, i.e., high antimicrobial activity, low cytotoxicity against human cells, stability against proteolytic degradation, and low costs of production. In the design of new AMPs, several physicochemical features, such as hydrophobicity, net positive charge, propensity to assume amphipathic conformation, and self-assembling properties, must be considered. Starting from the sequence of the dodecapeptide 1018-K6, we designed a new 10-aminoacid peptide, namely RiLK1, which is highly effective against both fungi and Gram-positive and -negative bacteria at low micromolar concentrations without causing human cell cytotoxicity. In order to find the structural reasons explaining the improved performance of RiLK1 versus 1018-K6, a comparative analysis of the two peptides was carried out with a combination of CD, NMR, and fluorescence spectroscopies, while their self-assembling properties were analyzed by optical and atomic force microscopies. Interestingly, the different spectroscopic and microscopic profiles exhibited by the two peptides, including the propensity of RiLK1 to adopt helix arrangements in contrast to 1018-K6, could explain the improved bactericidal, antifungal, and anti-biofilm activities shown by the new peptide against a panel of food pathogens.
Enhanced Stability of Detergent-Free Human Native STEAP1 Protein from Neoplastic Prostate Cancer Cells upon an Innovative Isolation Procedure
Authors: Barroca-Ferreira Jorge , Cruz-Vicente Pedro , Santos Marino F. A. , Rocha Sandra M. , Santos-Silva Teresa , Maia Cláudio J. , Passarinha Luís A.
Published: September 2021

Background: The STEAP1 is a cell-surface antigen over-expressed in prostate cancer, which contributes to tumor progression and aggressiveness. However, the molecular mechanisms underlying STEAP1 and its structural determinants remain elusive. Methods: The fraction capacity of Butyl- and Octyl-Sepharose matrices on LNCaP lysates was evaluated by manipulating the ionic strength of binding and elution phases, followed by a Co-Immunoprecipitation (Co-IP) polishing. Several potential stabilizing additives were assessed, and the melting temperature (Tm) values ranked the best/worst compounds. The secondary structure of STEAP1 was identified by circular dichroism. Results: The STEAP1 was not fully captured with 1.375 M (Butyl), in contrast with interfering heterologous proteins, which were strongly retained and mostly eluted with water. This single step demonstrated higher selectivity of Butyl-Sepharose for host impurities removal from injected crude samples. Co-IP allowed recovering a purified fraction of STEAP1 and contributed to unveil potential physiologically interacting counterparts with the target. A Tm of ~55 °C was determined, confirming STEAP1 stability in the purification buffer. A predominant α-helical structure was identified, ensuring the protein’s structural stability. Conclusions: A method for successfully isolating human STEAP1 from LNCaP cells was provided, avoiding the use of detergents to achieve stability, even outside a membrane-mimicking environment.
NGF Eye Administration Recovers the TrkB and Glutamate/GABA Marker Deficit in the Adult Visual Cortex Following Optic Nerve Crush
Authors: Rosso Pamela , Fico Elena , Mesentier-Louro Louise A. , Triaca Viviana , Lambiase Alessandro , Rama Paolo , Tirassa Paola
Published: September 2021

Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.
Impairment of the Hypothalamus–Pituitary–Thyroid Axis Caused by Naturally Occurring GATA2 Mutations In Vitro
Authors: Sakai Yuki , Ohba Kenji , Sasaki Shigekazu , Matsushita Akio , Nakamura Hiroko Misawa , Kuroda Go , Tsuriya Daisuke , Yamashita Miho , Suda Takafumi
Published: September 2021

The transcription factor GATA2 regulates gene expression in several cells and tissues, including hematopoietic tissues and the central nervous system. Recent studies revealed that loss-of-function mutations in GATA2 are associated with hematological disorders. Our earlier in vitro studies showed that GATA2 plays an essential role in the hypothalamus–pituitary–thyroid axis (HPT axis) by regulating the genes encoding prepro-thyrotropin-releasing hormone (preproTRH) and thyroid-stimulating hormone β (TSHβ). However, the effect of GATA2 mutants on the transcriptional activity of their promoters remains unelucidated. In this study, we created five human GATA2 mutations (R308P, T354M, R396Q, R398W, and S447R) that were reported to be associated with hematological disorders and analyzed their functional properties, including transactivation potential and DNA-binding capacity toward the preproTRH and the TSHβ promoters. Three mutations (T354M, R396Q, and R398W) within the C-terminal zinc-finger domain reduced the basal GATA2 transcriptional activity on both the preproTRH and the TSHβ promoters with a significant loss of DNA binding affinity. Interestingly, only the R398W mutation reduced the GATA2 protein expression. Subsequent analysis demonstrated that the R398W mutation possibly facilitated the GATA2 degradation process. R308P and S447R mutants exhibited decreased transcriptional activity under protein kinase C compared to the wild-type protein. In conclusion, we demonstrated that naturally occurring GATA2 mutations impair the HPT axis through differential functional mechanisms in vitro.
A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia
Authors: Büki Alexandra , Kekesi Gabriella , Horvath Gyongyi , Vécsei László
Published: September 2021

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms including autonomic imbalance. These disturbances involve almost all autonomic functions and might contribute to poor medication compliance, worsened quality of life and increased mortality. Therefore, it has a great importance to find a potential therapeutic solution to improve the autonomic disturbances. The altered level of kynurenines (e.g., kynurenic acid), as tryptophan metabolites, is almost the most consistently found biochemical abnormality in schizophrenia. Kynurenic acid influences different types of receptors, most of them involved in the pathophysiology of schizophrenia. Only few data suggest that kynurenines might have effects on multiple autonomic functions. Publications so far have discussed the implication of kynurenines and the alteration of the autonomic nervous system in schizophrenia independently from each other. Thus, the coupling between them has not yet been addressed in schizophrenia, although their direct common points, potential interfaces indicate the consideration of their interaction. The present review gathers autonomic disturbances, the impaired kynurenine pathway in schizophrenia, and the effects of kynurenine pathway on autonomic functions. In the last part of the review, the potential interaction between the two systems in schizophrenia, and the possible therapeutic options are discussed.
C3G Protein, a New Player in Glioblastoma
Authors: Manzano Sara , Gutierrez-Uzquiza Alvaro , Bragado Paloma , Cuesta Angel M , Guerrero Carmen , Porras Almudena
Published: September 2021

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.
Hybrid Deep Learning Based on a Heterogeneous Network Profile for Functional Annotations of Plasmodium falciparum Genes
Authors: Suratanee Apichat , Plaimas Kitiporn
Published: September 2021

Functional annotation of unknown function genes reveals unidentified functions that can enhance our understanding of complex genome communications. A common approach for inferring gene function involves the ortholog-based method. However, genetic data alone are often not enough to provide information for function annotation. Thus, integrating other sources of data can potentially increase the possibility of retrieving annotations. Network-based methods are efficient techniques for exploring interactions among genes and can be used for functional inference. In this study, we present an analysis framework for inferring the functions of Plasmodium falciparum genes based on connection profiles in a heterogeneous network between human and Plasmodium falciparum proteins. These profiles were fed into a hybrid deep learning algorithm to predict the orthologs of unknown function genes. The results show high performance of the model’s predictions, with an AUC of 0.89. One hundred and twenty-one predicted pairs with high prediction scores were selected for inferring the functions using statistical enrichment analysis. Using this method, PF3D7_1248700 and PF3D7_0401800 were found to be involved with muscle contraction and striated muscle tissue development, while PF3D7_1303800 and PF3D7_1201000 were found to be related to protein dephosphorylation. In conclusion, combining a heterogeneous network and a hybrid deep learning technique can allow us to identify unknown gene functions of malaria parasites. This approach is generalized and can be applied to other diseases that enhance the field of biomedical science.
An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease
Authors: Dakhel Sheila , Lizak Christian , Matasci Mattia , Mock Jacqueline , Villa Alessandra , Neri Dario , Cazzamalli Samuele
Published: September 2021

Antibody-cytokine fusion proteins (immunocytokines) are gaining importance for cancer therapy, but those products are often limited by systemic toxicity related to the activity of the cytokine payload in circulation and in secondary lymphoid organs. Tumor necrosis factor (TNF) is used as a pro-inflammatory payload to trigger haemorrhagic necrosis and boost anti-cancer immunity at the tumor site. Here we describe a depotentiated version of TNF (carrying the single point mutation I97A), which displayed reduced binding affinity to its cognate receptor tumor necrosis factor receptor 1 (TNFR-1) and lower biocidal activity. The fusion of the TNF(I97A) mutant to the L19 antibody promoted restoration of anti-tumor activity upon accumulation on the cognate antigen, the alternatively spliced EDB domain of fibronectin. In vivo administration of high doses (375 μg/Kg) of the fusion protein showed a potent anti-tumor effect without apparent toxicity compared with the wild type protein. L19-TNFI97A holds promise for the targeted delivery of TNF activity to neoplastic lesions, helping spare normal tissues.
PolyPurine Reverse Hoogsteen Hairpins Work as RNA Species for Gene Silencing
Authors: Aubets Eva , Chillon Miguel , Ciudad Carlos J. , Noé Véronique
Published: September 2021

PolyPurine Reverse Hoogsteen Hairpins (PPRHs) are gene-silencing DNA-oligonucleotides developed in our laboratory that are formed by two antiparallel polypurine mirror repeat domains bound intramolecularly by Hoogsteen bonds. The aim of this work was to explore the feasibility of using viral vectors to deliver PPRHs as a gene therapy tool. After treatment with synthetic RNA, plasmid transfection, or viral infection targeting the survivin gene, viability was determined by the MTT assay, mRNA was determined by RT-qPCR, and protein levels were determined by Western blot. We showed that the RNA-PPRH induced a decrease in cell viability in a dose-dependent manner and an increase in apoptosis in PC-3 and HeLa cells. Both synthetic RNA-PPRH and RNA-PPRH intracellularly generated upon the transfection of a plasmid vector were able to reduce survivin mRNA and protein levels in PC-3 cells. An adenovirus type-5 vector encoding the PPRH against survivin was also able to decrease survivin mRNA and protein levels, leading to a reduction in HeLa cell viability. In this work, we demonstrated that PPRHs can also work as RNA species, either chemically synthesized, transcribed from a plasmid construct, or transcribed from viral vectors. Therefore, all these results are the proof of principle that viral vectors could be considered as a delivery system for PPRHs.
Potential of Vasoprotectives to Inhibit Non-Enzymatic Protein Glycation, and Reactive Carbonyl and Oxygen Species Uptake
Authors: Bednarska Katarzyna , Fecka Izabela
Published: September 2021

Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or glyoxal (GO) are the main precursors of the formation of advanced glycation end products (AGEs). AGEs are a major factor in the development of vascular complications in diabetes. Vasoprotectives (VPs) exhibit a wide range of activities beneficial to cardiovascular health. The present study aimed to investigate selected VPs and their structural analogs for their ability to trap MGO/GO, inhibit AGE formation, and evaluate their antioxidant potential. Ultra-high-performance liquid chromatography coupled with an electrospray ionization mass spectrometer (UHPLC-ESI-MS) and diode-array detector (UHPLC-DAD) was used to investigate direct trapping capacity and kinetics of quenching MGO/GO, respectively. Fluorimetric and colorimetric measurements were used to evaluate antiglycation and antioxidant action. All tested substances showed antiglycative effects, but hesperetin was the most effective in RCS scavenging. We demonstrated that rutin, diosmetin, hesperidin, and hesperetin could trap both MGO and GO by forming adducts, whose structures we proposed. MGO-derived AGE formation was inhibited the most by hesperetin, and GO-derived AGEs by diosmetin. High reducing and antiradical activity was confirmed for quercetin, rutin, hesperetin, and calcium dobesilate. Therefore, in addition to other therapeutic applications, some VPs could be potential candidates as antiglycative agents to prevent AGE-related complications of diabetes.
Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy
Authors: Balikov Daniel A. , Hu Kevin , Liu Chia-Jen , Betz Bryan L. , Chinnaiyan Arul M. , Devisetty Laxmi V. , Venneti Sriram , Tomlins Scott A. , Cani Andi K. , Rao Rajesh C.
Published: September 2021

Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal CDKN2A deep deletions, a highly recurrent alteration in VRL patients, as well as MYD88 p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes SETD2, BRCA2, TERT, and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.