bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging the Potential of Digital Technology for Better Individualized Treatment of Parkinson's Disease
Authors: Fröhlich Holger , Bontridder Noémi , Petrovska-Delacréta Dijana , Glaab Enrico , Kluge Felix , Yacoubi Mounim El , Marín Valero Mayca , Corvol Jean-Christophe , Eskofier Bjoern , Van Gyseghem Jean-Marc , Lehericy Stepháne , Winkler Jürgen , Klucken Jochen
Published: February 2022

Recent years have witnessed a strongly increasing interest in digital technology within medicine (sensor devices, specific smartphone apps) and specifically also neurology. Quantitative measures derived from digital technology could provide Digital Biomarkers (DMs) enabling a quantitative and continuous monitoring of disease symptoms, also outside clinics. This includes the possibility to continuously and sensitively monitor the response to treatment, hence opening the opportunity to adapt medication pathways quickly. In addition, DMs may in the future allow early diagnosis, stratification of patient subgroups and prediction of clinical outcomes. Thus, DMs could complement or in certain cases even replace classical examiner-based outcome measures and molecular biomarkers measured in cerebral spinal fluid, blood, urine, saliva, or other body liquids. Altogether, DMs could play a prominent role in the emerging field of precision medicine. However, realizing this vision requires dedicated research. First, advanced data analytical methods need to be developed and applied, which extract candidate DMs from raw signals. Second, these candidate DMs need to be validated by (a) showing their correlation to established clinical outcome measures, and (b) demonstrating their diagnostic and/or prognostic value compared to established biomarkers. These points again require the use of advanced data analytical methods, including machine learning. In addition, the arising ethical, legal and social questions associated with the collection and processing of sensitive patient data and the use of machine learning methods to analyze these data for better individualized treatment of the disease, must be considered thoroughly. Using Parkinson's Disease (PD) as a prime example of a complex multifactorial disorder, the purpose of this article is to critically review the current state of research regarding the use of DMs, discuss open challenges and highlight emerging new directions.
Vaccine Response in Patients With Multiple Sclerosis Receiving Teriflunomide
Authors: Tornatore Carlo , Wiendl Heinz , Lublin Alex L. , Geertsen Svend S. , Chavin Jeffrey , Truffinet Philippe , Bar-Or Amit
Published: February 2022

Many patients with multiple sclerosis (MS) receive disease-modifying therapies (DMTs), such as teriflunomide, to reduce disease activity and slow progression. DMTs mediate their efficacy by modulating or suppressing the immune system, which might affect a patient's response to vaccination. As vaccines against the SARS-CoV-2 virus become available, questions have arisen around their efficacy and safety for patients with MS who are receiving DMTs. Data are beginning to emerge regarding the potential influence of certain DMTs on a patient's response to coronavirus disease 2019 (COVID-19) vaccines and are supported by evidence from vaccination studies of other pathogens. This review summarizes the available data on the response to vaccines in patients with MS who are receiving DMTs, with a focus on teriflunomide. It also provides an overview of the leading COVID-19 vaccines and current guidance around COVID-19 vaccination for patients with MS. Though few vaccination studies have been done for this patient population, teriflunomide appears to have minimal influence on the response to seasonal influenza vaccine. The evidence for other DMTs (e.g., fingolimod, glatiramer acetate) is less consistent: some studies suggest no effect of DMTs on vaccine response, whereas others show reduced vaccine efficacy. No unexpected safety signals have emerged in any vaccine study. Current guidance for patients with MS is to continue DMTs during COVID-19 vaccination, though adjusted timing of dosing for some DMTs may improve the vaccine response.
Cerebral Energy Status and Altered Metabolism in Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage: A Prospective 31P-MRS Pilot Study
Authors: Treichl Stephanie Alice , Ho Wing Mann , Steiger Ruth , Grams Astrid Ellen , Rietzler Andreas , Luger Markus , Gizewski Elke Ruth , Thomé Claudius , Petr Ondra
Published: February 2022

Background

Acute changes of cerebral energy metabolism in early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) may play a crucial role for overall neurological outcome. However, direct detection of these alterations is limited. Phosphorous magnetic resonance spectroscopy (31P-MRS) is a molecular-based advanced neuroimaging technique allowing measurements of pathophysiological processes and tissue metabolism based on various phosphorous compound metabolites. This method may provide objective assessment of both primary and secondary changes.

Objective

The aim of this pilot study was to evaluate the feasibility and the diagnostic potential of early 31P-MRS in aSAH.

Methods

Patients with aSAH treated for ruptured aneurysms between July 2016 and October 2017 were prospectively included in the study. 3-Tesla-MRI including 31P-MRS was performed within the first 72 h after hemorrhage. Data of the vascular territories of the anterior, middle, and posterior cerebral arteries (ACA, MCA, PCA) and the basal ganglia were separately analyzed and compared with data of a healthy age- and sex-matched control group. Phosphorous compound metabolites were quantified, and ratios of these metabolites were further evaluated. Influence of treatment modality, clinical conditions, and analgosedation were analyzed.

Results

Data of 13 patients were analyzed. 31P-MRS showed significant changes in cerebral energy metabolism after aSAH in all cerebrovascular territories. Both PCr/ATP and PCr/Pi ratio were notably increased (P < 0.001). Also, Pi/ATP was significantly decreased in all cerebrovascular territories (P = 0.014). PME/PDE ratio was overall significant decreased (P < 0.001).

Conclusion

31P-MRS is a promising non-invasive imaging tool for the assessment of changes in energy metabolism after aSAH. It allows a detailed insight into EBI and seems to harbor a high potential for clinical practice.
Sulcal Cavitation in Linear Head Acceleration: Possible Correlation With Chronic Traumatic Encephalopathy
Authors: Kerwin Joseph , Yücesoy Atacan , Vidhate Suhas , Dávila-Montero Bianca M. , Van Orman Jacob L. , Pence Thomas J. , Tartis Michaelann , Mejía-Alvarez Ricardo , Willis Adam M.
Published: February 2022

Traumatic Brain Injury (TBI) is a significant public health and financial concern that is affecting tens of thousands of people in the United States annually. There were over a million hospital visits related to TBI in 2017. Along with immediate and short-term morbidity from TBI, chronic traumatic encephalopathy (CTE) can have life-altering, chronic morbidity, yet the direct linkage of how head impacts lead to this pathology remains unknown. A possible clue is that chronic traumatic encephalopathy appears to initiate in the depths of the sulci. The purpose of this study was to isolate the injury mechanism/s associated with blunt force impact events. To this end, drop tower experiments were performed on a human head phantom. Our phantom was fabricated into a three-dimensional extruded ellipsoid geometry made out of Polyacrylamide gelatin that incorporated gyri-sulci interaction. The phantom was assembled into a polylactic acid 3D-printed skull, surrounded with deionized water, and enclosed between two optical windows. The phantom received repetitive low-force impacts on the order of magnitude of an average boxing punch. Intracranial pressure profiles were recorded in conjunction with high-speed imaging, 25 k frames-per-second. Cavitation was observed in all trials. Cavitation is the spontaneous formation of vapor bubbles in the liquid phase resulting from a pressure drop that reaches the vapor pressure of the liquid. The observed cavitation was predominately located in the contrecoup during negative pressure phases of local intracranial pressure. To further investigate the cavitation interaction with the brain tissue phantom, a 2D plane strain computational model was built to simulate the deformation of gyrated tissue as a result from the initiation of cavitation bubbles seen in the phantom experiments. These computational experiments demonstrated a focusing of strain at the depths of the sulci from bubble expansion. Our results add further evidence that mechanical interactions could contribute to the development of chronic traumatic encephalopathy and also that fluid cavitation may play a role in this interaction.
Motor Conduction Studies and Handgrip in Hereditary TTR Amyloidosis: Simple Tools to Evaluate the Upper Limbs
Authors: Di Stefano Vincenzo , Thomas Ewan , Giustino Valerio , Iacono Salvatore , Torrente Angelo , Pillitteri Guglielmo , Gagliardo Andrea , Lupica Antonino , Palma Antonio , Battaglia Giuseppe , Brighina Filippo
Published: February 2022

Purpose

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is caused by mutations in theTTRgene, leading to misfolded monomers that aggregate generating amyloid fibrils. The clinical phenotype is heterogeneous, and characterized by a multisystemic disease affecting the sensorimotor and autonomic functions along with other organs.

Materials and Methods

All the patients were assessed by complete neurological assessment, neurophysiological evaluation, of the median nerve, and handgrip analysis. The data are presented as means and standard deviations. Parametric and non-parametric assessments have been performed to identify differences between groups. Pearson's correlation has been carried out when appropriate.

Results

Twenty patients with ATTRv (66.1 ± 8.4 years; eight females) and 30 controls (61.1 ± 11.6 years; 16 females) were enrolled. Handgrip strength was reduced in patients with ATTR in both right and left hands compared to the controls. Significant differences were found between patients and controls in the right (handgrip right, HGSRTTR 21.1 ± 13 kg vs. HGSRControl 29.4 ± 11.3 kg,p= 0.017) and left (handgrip left, HGSLTTR 22.2 ± 10.7 kg. vs. HGSLControl 31 ± 11.3 kg,p= 0.007). NIS and CMAP amplitude of the median nerve were related to HGS measures for both hands in patients with ATTRv.

Conclusions

The progression of bilateral carpal tunnel syndrome is related to neurophysiological data in the median nerve in ATTRv. Also, handgrip measures might represent an important tool for the assessment of disease progression in ATTRv. We propose using a combination of CMAP amplitude and HGS for the assessment of hand motor strength in ATTRv.
Differential Role of Sex and Age in the Synaptic Transmission of Degus (Octodon degus)
Authors: Oliva Carolina A. , Rivera Daniela S. , Mariqueo Trinidad A. , Bozinovic Francisco , Inestrosa Nibaldo C.
Published: February 2022

Octodon degus are a diurnal long-lived social animal widely used to perform longitudinal studies and complex cognitive tasks to test for physiological conditions with similitude in human behavior. They show a complex social organization feasible to be studied under different conditions and ages. Several aspects in degus physiology demonstrated that these animals are susceptible to environmental conditions, such as stress, fear, feeding quality, and isolation. However, the relevance of these factors in life of this animal depends on sex and age. Despite its significance, there are few studies with the intent to characterize neurological parameters that include these two parameters. To determine the basal neurophysiological status, we analyzed basic electrophysiological parameters generated during basal activity or synaptic plasticity in the brain slices of young and aged female and male degus. We studied the hippocampal circuit of animals kept in social ambient in captivity under controlled conditions. The study of basal synaptic activity in young animals (12–24 months old) was similar between sexes, but female degus showed more efficient synaptic transmission than male degus. We found the opposite in aged animals (60–84 months old), where male degus had a more efficient basal transmission and facilitation index than female degus. Furthermore, female and male degus develop significant but not different long-term synaptic plasticity (LTP). However, aged female degus need to recruit twice as many axons to evoke the same postsynaptic activity as male degus and four times more when compared to young female degus. These data suggest that, unlike male degus, the neural status of aged female degus change, showing less number or functional axons available at advanced ages. Our data represent the first approach to incorporate the effect of sex along with age progression in basal neural status.
Tryptophan Metabolites as Biomarkers for Esophageal Cancer Susceptibility, Metastasis, and Prognosis
Authors: Chen Yun , Chen Jianliang , Guo Dainian , Yang Peixuan , Chen Shuang , Zhao Chengkuan , Xu Chengcheng , Zhang Qiuzhen , Lin Chaoxian , Zhong Shilong , Zhang Shuyao
Published: February 2022

Background

Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.

Method

A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.

Results

Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively).

Conclusion

This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.
Case Report: Opportunities and Challenges of Immunotherapy in Heavily-Treated EGFR-Mutant Advanced Squamous Cell Lung Carcinoma After Progression on EGFR-TKIs and Chemotherapy
Authors: Jin Wei , Wang Xin , Wang Jie , Lin Lin
Published: February 2022

Background

Epidermal growth factor receptor (EGFR) mutations have a low incidence in squamous cell lung cancer (SqCLC), and the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated SqCLC is far less than that in EGFR-mutated lung adenocarcinoma. The treatment strategy for patients with EGFR-mutated non-small cell lung cancer who are refractory to EGFR TKIs has become a current dilemma and challenge.

Case Presentation

A case of a 69-year-old male patient suffering from intermittent cough and hemoptysis was diagnosed with EGFR-mutated advanced SqCLC (stage cT2bN2M1). The patient was treated with camrelizumab alone after five courses of different systemic therapies and achieved a partial response, with an eminent progression-free survival of more than 24 months. Grade 1 to 2 reactive cutaneous capillary endothelial proliferation and mild pruritus were observed during the treatment. No other immune-related adverse events were observed.

Conclusion

Monotherapy of immune-checkpoint inhibitors may be considered as a later-line option for EGFR-mutated advanced SqCLC patients with PD-L1 expression.
Impact of an Embedded Palliative Care Clinic on Healthcare Utilization for Patients With a New Thoracic Malignancy
Authors: Gast Kelly C. , Benedict Jason A. , Grogan Madison , Janse Sarah , Saphire Maureen , Kumar Pooja , Bertino Erin M. , Agne Julia L. , Presley Carolyn J.
Published: February 2022

Introduction

Palliative care is beneficial for patients with advanced lung cancer, but the optimal model of palliative care delivery is unknown. We investigated healthcare utilization before and after embedding a palliative care physician within a thoracic medical oncology “onco-pall” clinic.

Methods

This is a retrospective cross-sectional cohort study comparing healthcare outcomes in two cohorts: “pre-cohort” 12 months prior to and “post-cohort” 12-months after the onco-pall clinic start date. Patients were included if they had a new diagnosis of lung cancer and received care at The Ohio State University Thoracic Oncology Center, and resided in Franklin County or 6 adjacent counties. During the pre-cohort time period, access to palliative care was available at a stand-alone palliative care clinic. Palliative care intervention in both cohorts included symptom assessment and management, advance care planning, and goals of care discussion as appropriate. Outcomes evaluated included rates of emergency department (ED) visits, hospital admissions, 30-day readmissions, and intensive care unit (ICU) admissions. Estimates were calculated in rates per-person-years and with Poisson regression models.

Results

In total, 474 patients met criteria for analysis (214 patients included in the pre-cohort and 260 patients in the post-cohort). Among all patients, 52% were male and 48% were female with a median age of 65 years (range 31-92). Most patients had non-small cell lung cancer (NSCLC - 17% stage 1-2, 20% stage 3, 47% stage 4) and 16% had small cell lung cancer. The post-cohort was older [median age 66 years vs 63 years in the pre-cohort (p-value: < 0.01)]. The post-cohort had a 26% reduction in ED visits compared to the pre-cohort, controlling for age, race, marital status, sex, county, Charlson score at baseline, cancer type and stage (adjusted relative risk: aRR: 0.74, 95% CI: 0.58-0.94, p-value = 0.01). Although not statistically significant, there was a 29% decrease in ICU admissions (aRR: 0.71, 95% CI: 0.41-1.21, p-value = 0.21) and a 15% decrease in hospital admissions (aRR: 0.85, 95% CI: 0.70-1.03, p-value = 0.10). There was no difference in 30-day readmissions (aRR: 1.03, 95% CI: 0.73-1.45, p-value = 0.85).

Conclusions

Embedding palliative care clinics within medical oncology clinics may decrease healthcare utilization for patients with thoracic malignancies. Further evaluation of this model is warranted.
How Best to Play the Role of Tumor Deposits in Stage III Colon Cancer?
Authors: Liu Yunxiao , Zhang Hao , Wang Yuliuming , Wang Chunlin , Xiong Huan , Wang Yang , Jing Haoyu , Jiang Xia , Hu Hanqing , Tang Qingchao , Wang Guiyu
Published: February 2022

Background

The purpose of this study is to comprehensively evaluate the prognostic role of tumor deposits (TD) in stage III colon cancer.

Methods

24,600 CC patients with III stage colon cancer were collected from the Surveillance, Epidemiology, and End Result (SEER) database and 618 CC patients from the Second Affiliated Hospital of Harbin Medical University. All patients were divided into development, internal, and external validation cohorts. The combination of positive lymph nodes (PLN) and the status or number of TD was defined as modified pN (mpN) and novel pN (npN). The Cox proportional hazard regression model was used to analyze the relationship between cancer-specific survival (CSS) and mpN or npN. CSS stratified by pN, mpN, and npN was analyzed by the Kaplan–Meier curves. The area under the receiver operating characteristic curve (AUC) was used to demonstrate the predictive abilities of the pN, mpN, and npN stages. The validation cohorts were used to validate the results.

Results

The Cox proportional hazard regression model showed that mpN and npN were an independent prognostic factor for CSS. AUC showed that the predictive accuracy of mpN was better than that of the pN stage for 5-year CSS in the development (0.621 vs. 0.609, p < 0.001) and internal validation cohorts (0.618 vs. 0.612, p = 0.016) and the npN was also better than the pN stage for 5-year CSS in the development (0.623 vs. 0.609, p < 0.001) and internal validation cohorts (0.620 vs. 0.612, p = 0.001). However, there was no significant difference between the AUCs of mpN and npN. Moreover, the pN stage for 5-year CSS in the external validation cohort is 0.606 vs. 0.563, p = 0.045.

Conclusions

In stage III CC, mpN and npN may be superior to the pN stage in assessing prognosis, suggesting that the TD information should be included in the pN stage.
Breathing Patterns and Oxygenation Saturation During Sleep in Children Habitually Living at High Altitude in the Andes: A Systematic Review
Authors: Ucrós Santiago , Castro-Guevara Javier A. , Hill Catherine M. , Castro-Rodriguez Jose A.
Published: February 2022

Background

Human respiratory physiology changes significantly in high altitude settings and these changes are particularly marked during sleep. It is estimated that 170 million people live above 2,500 m in environments where normal sleep parameters differ from those established at sea level or low altitude.

Methods

We conducted a systematic review of publications reporting sleep studies in healthy children living at high altitude. For this purpose, data from PubMed, EMBASE, SciELO and Epistemomikos bases were retrieved up to August 2021.

Results

Six articles met specified inclusion criteria; all reporting data were from South America involving 245 children (404 sleep studies) in children aged 0.6 months to 18 years, at altitudes between 2,560 to 3,775 m. The main results were: (1) Central apnea index decreased as the age increased. (2) The obstructive apnea/hypopnea index showed a bimodal profile with an increase in young infants up to age of 4 months, decreasing to 15 months of age, and then a second peak in children aged 4 to 9 years of age, dropping in older schoolchildren and adolescents. (3) Periodic breathing in the first months of life is more marked with increasing altitude and decreases with age.

Conclusions

There are few studies of sleep physiology in children living at high altitude. The international parameters defining normal apnea indices currently used at low altitude cannot be applied to high altitude settings. The interpretation of sleep studies in children living at high altitude is complex because there are important developmental changes across childhood and a wide range of altitude locations. More normative data are required to determine thresholds for respiratory pathology at a variety of high altitude settings.
Implementation and Evaluation of Resuscitation Training for Childcare Workers
Authors: Michel Jörg , Ilg Tim , Neunhoeffer Felix , Hofbeck Michael , Heimberg Ellen
Published: February 2022

Background and Objective

Children spend a large amount of time in daycare centers or schools. Therefore, it makes sense to train caregivers well in first-aid measures in children. The aim of this study is to evaluate whether a multimodal resuscitation training for childcare workers can teach adherence to resuscitation guidelines in a sustainable way.

Materials and Methods

Caregivers at a daycare center who had previously completed a first-aid course received a newly developed multimodal resuscitation training in small groups of 7–8 participants by 3 AHA certified PALS instructors and providers. The 4-h focused retraining consisted of a theoretical component, expert modeling, resuscitation exercises on pediatric manikins (Laerdal Resusci Baby QCPR), and simulated emergency scenarios. Adherence to resuscitation guidelines was compared before retraining, immediately after training, and after 6 months. This included evaluation of chest compressions per round, chest compression rate, compression depth, full chest recoil, no-flow time, and success of rescue breaths. For better comparability and interpretation of the results, the parameters were evaluated both separately and summarized in a resuscitation score reflecting the overall adherence to the guidelines.

Results

A total of 101 simulated cardiopulmonary resuscitations were evaluated in 39 participants. In comparison to pre-retraining, chest compressions per round (15.0 [10.0–29.0] vs. 30.0 [30.0–30.0], p < 0.001), chest compression rate (100.0 [75.0–120.0] vs. 112.5 [105–120.0], p < 0.001), correct compression depth (6.7% [0.0–100.0] vs. 100.0% [100.0–100.0], p < 0.001), no-flow time (7.0 s. [5.0–9.0] vs. 4.0 s. [3.0–5.0], p < 0.001), success of rescue breaths (0.0% [0.0–0.0] vs. 100.0% [100.0–100.0], p < 0.001), and resuscitation score were significantly improved immediately after training (3.9 [3.2–4.9] vs. 6.3 [5.6–6.7], p < 0.001). At follow-up, there was no significant change in chest compression rate and success of rescue breaths. Chest compressions per round (30.0 [15.0–30.0], p < 0.001), no-flow time (5.0 s. [4.0–8.0], p < 0.001), compression depths (100.0% [96.7–100.0], p < 0.001), and resuscitation score worsened again after 6 months (5.7 [4.7–6.4], p = 0.03). However, the results were still significantly better compared to pre-retraining.

Conclusion

Our multimodal cardiopulmonary resuscitation training program for caregivers is effective to increase the resuscitation performance immediately after training. Although the effect diminishes after 6 months, adherence to resuscitation guidelines was significantly better than before retraining.
Candidate Therapeutics by Screening for Multitargeting Ligands: Combining the CB2 Receptor With CB1, PPARγ and 5-HT4 Receptors
Authors: El-Atawneh Shayma , Goldblum Amiram
Published: February 2022

In recent years, the cannabinoid type 2 receptor (CB2R) has become a major target for treating many disease conditions. The old therapeutic paradigm of “one disease-one target-one drug” is being transformed to “complex disease-many targets-one drug.” Multitargeting, therefore, attracts much attention as a promising approach. We thus focus on designing single multitargeting agents (MTAs), which have many advantages over combined therapies. Using our ligand-based approach, the “Iterative Stochastic Elimination” (ISE) algorithm, we produce activity models of agonists and antagonists for desired therapeutic targets and anti-targets. These models are used for sequential virtual screening and scoring large libraries of molecules in order to pick top-scored candidates for testing in vitro and in vivo. In this study, we built activity models for CB2R and other targets for combinations that could be used for several indications. Those additional targets are the cannabinoid 1 receptor (CB1R), peroxisome proliferator-activated receptor gamma (PPARγ), and 5-Hydroxytryptamine receptor 4 (5-HT4R). All these models have high statistical parameters and are reliable. Many more CB2R/CBIR agonists were found than combined CB2R agonists with CB1R antagonist activity (by 200 fold). CB2R agonism combined with PPARγ or 5-HT4R agonist activity may be used for treating Inflammatory Bowel Disease (IBD). Combining CB2R agonism with 5-HT4R generates more candidates (14,008) than combining CB2R agonism with agonists for the nuclear receptor PPARγ (374 candidates) from an initial set of ∼2.1 million molecules. Improved enrichment of true vs. false positives may be achieved by requiring a better ISE score cutoff or by performing docking. Those candidates can be purchased and tested experimentally to validate their activity. Further, we performed docking to CB2R structures and found lower statistical performance of the docking (“structure-based”) compared to ISE modeling (“ligand-based”). Therefore, ISE modeling may be a better starting point for molecular discovery than docking.
Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis
Authors: Smeda Marta , Stojak Marta , Przyborowski Kamil , Sternak Magdalena , Suraj-Prazmowska Joanna , Kus Kamil , Derszniak Katarzyna , Jasztal Agnieszka , Kij Agnieszka , Kurpinska Anna , Kieronska-Rudek Anna , Wojnar-Lason Kamila , Buczek Elzbieta , Mohaissen Tasnim , Chlopicki Stefan
Published: February 2022

Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.
Physical Exercise in the Context of Air Pollution: An Emerging Research Topic
Authors: You Yanwei , Wang Dizhi , Liu Jianxiu , Chen Yuquan , Ma Xindong , Li Wenkai
Published: February 2022

Physical exercise (PE) brings physiological benefits to human health; paradoxically, exposure to air pollution (AP) is harmful. Hence, the combined effects of AP and PE are interesting issues worth exploring. The objective of this study is to review literature involved in AP-PE fields to perform a knowledge-map analysis and explore the collaborations, current hotspots, physiological applications, and future perspectives. Herein, cluster, co-citation, and co-occurrence analysis were applied using CiteSpace and VOSviewer software. The results demonstrated that AP-PE domains have been springing up and in rapid growth since the 21st century. Subsequently, active countries and institutions were identified, and the productive institutions were mainly located in USA, China, UK, Spain, and Canada. Developed countries seemed to be the major promoters. Additionally, subject analysis found that environmental science, public health, and sports medicine were the core subjects, and multidimensional communications were forming. Thereafter, a holistic presentation of reference co-citation clusters was conducted to discover the research topics and trace the development focuses. Youth, elite athletes, and rural population were regarded as the noteworthy subjects. Commuter exposure and moderate aerobic exercise represented the common research context and exercise strategy, respectively. Simultaneously, the research hotspots and application fields were elaborated by keyword co-occurrence distribution. It was noted that physiological adaptations including respiratory, cardiovascular, metabolic, and mental health were the major themes; oxidative stress and inflammatory response were the mostly referred mechanisms. Finally, several challenges were proposed, which are beneficial to promote the development of the research field. Molecular mechanisms and specific pathways are still unknown and the equilibrium points and dose-effect relationships remain to be further explored. We are highly confident that this study provides a unique perspective to systematically and comprehensively review the pieces of AP-PE research and its related physiological mechanisms for future investigations.
Oxidative Damage Is Influenced by Diet But Unaffected by Selection for Early Age of Oviposition in the Marula Fly, Ceratitis cosyra (Diptera: Tephritidae)
Authors: Malod Kevin , du Rand Esther E. , Archer C. Ruth , Nicolson Susan W. , Weldon Christopher W.
Published: February 2022

The expression of life-history traits, such as lifespan or reproductive effort, is tightly correlated with the amount and blend of macronutrients that individuals consume. In a range of herbivorous insects, consuming high protein to carbohydrate ratios (P:C) decreases lifespan but increases female fecundity. In other words, females face a resource-based trade-off between lifespan and fecundity. Redox metabolism may help mediate this trade-off, if oxidative damage is elevated by reproductive investment and if this damage, in turn, reduces lifespan. Here, we test how diets varying in P:C ratio affect oxidative damage and antioxidant protection in female and male of the marula fly, Ceratitis cosyra (Diptera: Tephritidae). We use replicated lines that have been subjected to experimental evolution and differ in their lifespan and reproductive scheduling. We predicted that high fecundity would be associated with high oxidative damage and reduced antioxidant defences, while longer lived flies would show reduced damage and elevated antioxidant defences. However, higher levels of oxidative damage were observed in long-lived control lines than selection lines, but only when fed the diet promoting lifespan. Flies fed diets promoting female fecundity (1:4 and 1:2 P:C) suffered greater oxidative damage to lipids than flies fed the best diet (0:1 P:C) for lifespan. Total antioxidant capacity was not affected by the selection regime or nutrition. Our results reiterate the importance of nutrition in affecting life-history traits, but suggest that in C. cosyra, reactive oxygen species play a minimal role in mediating dietary trade-offs between lifespan and reproduction.
Missing Links Between Gene Function and Physiology in Genomics
Authors: Collado-Vides Julio , Gaudet Pascale , de Lorenzo Víctor
Published: February 2022

Knowledge of biological organisms at the molecular level that has been gathered is now organized into databases, often within ontological frameworks. To enable computational comparisons of annotations across different genomes and organisms, controlled vocabularies have been essential, as is the case in the functional annotation classifications used for bacteria, such as MultiFun and the more widely used Gene Ontology. The function of individual gene products as well as the processes in which collections of them participate constitute a wealth of classes that describe the biological role of gene products in a large number of organisms in the three kingdoms of life. In this contribution, we highlight from a qualitative perspective some limitations of these frameworks and discuss challenges that need to be addressed to bridge the gap between annotation as currently captured by ontologies and databases and our understanding of the basic principles in the organization and functioning of organisms; we illustrate these challenges with some examples in bacteria. We hope that raising awareness of these issues will encourage users of Gene Ontology and similar ontologies to be careful about data interpretation and lead to improved data representation.
The Effect of Resistance Training on Motor Unit Firing Properties: A Systematic Review and Meta-Analysis
Authors: Elgueta-Cancino Edith , Evans Ethan , Martinez-Valdes Eduardo , Falla Deborah
Published: February 2022

While neural changes are thought to be responsible for early increases in strength following resistance training (RT), the exact changes in motor unit (MU) firing properties remain unclear. This review aims to synthesize the available evidence on the effect of RT on MU firing properties. MEDLINE (OVID interface), EMBASE (OVID interface), Web of Science (all databases), Cochrane Library, EBSCO CINAHL Plus, PubMed, and EBSCO SportDiscus were searched from inception until June 2021. Randomized controlled trials and non-randomized studies of interventions that compared RT to no intervention (control) were included. Two reviewers independently extracted data from each trial, assessed the risk of bias and rated the cumulative quality of evidence. Motor unit discharge rate (MUDR), motor unit recruitment threshold (MURT), motor unit discharge rate variability (MUDRV), MU discharge rate at recruitment vs. recruitment threshold relationship, and MU discharge rate vs. recruitment threshold relationship were assessed. Seven trials including 167 participants met the inclusion criteria. Meta-analysis (four studies) revealed that MUDR did not change significantly (P = 0.43), but with considerable heterogeneity likely to be present (I2 = 91). Low to moderate evidence supports changes in MUDRV, MUDR at recruitment vs. recruitment threshold relationship, and the MUDR vs. recruitment threshold relationship. Overall, this systematic review revealed that there is a lack of high-quality evidence for the effect of RT on MU firing properties. Heterogeneity across studies undermines the quality of the evidence for multiple outcomes and affects the conclusions that can be drawn.
Identification of Odorant-Binding and Chemosensory Protein Genes in Mythimna separata Adult Brains Using Transcriptome Analyses
Authors: Chen Wen-Bo , Du Li-Xiao , Gao Xiao-Yan , Sun Long-Long , Chen Lin-Lin , Xie Gui-Ying , An Shi-Heng , Zhao Xin-Cheng
Published: February 2022

Large numbers of chemosensory genes have been identified in the peripheral sensory organs of the pest Mythimna separata (Walker) to increase our understanding of chemoreception-related molecular mechanisms and to identify molecular targets for pest control. Chemosensory-related genes are expressed in various tissues, including non-sensory organs, and they play diverse roles. To better understand the functions of chemosensory-related genes in non-sensory organs, transcriptomic analyses of M. separata brains were performed. In total, 29 odorant-binding proteins (OBPs) and 16 chemosensory proteins (CSPs) putative genes were identified in the transcriptomic data set. The further examination of sex- and tissue-specific expression using RT-PCR suggested that eight OBPs (OBP5, -7, -11, -13, -16, -18, -21, and -24) and eight CSPs (CSP2–4, -8, CSP10–12, and -15) genes were expressed in the brain. Furthermore, bands representing most OBPs and CSPs could be detected in antennae, except for a few that underwent sex-biased expression in abdomens, legs, or wings. An RT-qPCR analysis of the expression profiles of six OBPs (OBP3–5, -9, -10, and -16) and two CSPs (CSP3 and CSP4) in different tissues and sexes indicated that OBP16 was highly expressed in male brain, and CSP3 and CSP4 were female-biased and highly expressed in brain. The expression levels of OBP5 and OBP10 in brain were not significantly different between the sexes. The findings expand our current understanding of the expression patterns of OBPs and CSPs in M. separata sensory and non-sensory tissues. These results provide valuable reference data for exploring novel functions of OBPs and CSPs in M. separata and may help in developing effective biological control strategies for managing this pest by exploring novel molecular targets.
Advances in Understanding the Causes, Molecular Mechanism, and Perspectives of Russeting on Tree Fruit
Authors: Jiang Shenghui , Chen Min , Wang Ziqi , Ren Yanxue , Wang Bin , Zhu Jun , Zhang Yugang
Published: February 2022

The external quality of fruit is one of its most important qualities; good external quality attracts consumers easily and increases the value of fruit. Fruit russeting is one of the factors that influences the external quality of fruit and has been studied in most horticultural plants. However, the molecular mechanism of russeting has never been discussed so far. In this review, we summarize the research progress on fruit russeting, including causes, microscopic histomorphology, composition, genetics, and regulation and made a series of elaboration on the current research on fruit russeting. This study aims to provide insights into the mechanisms underlying fruit russeting. It also puts forward ideas for research on fruit russeting, which may provide a reference for future research.
Values, Motives, and Organic Food Consumption in China: A Moderating Role of Perceived Uncertainty
Authors: Wei Sheng , Liu Furong , She Shengxiang , Wu Rong
Published: February 2022

The present research attempts to understand the importance of altruistic and egoistic values in determining consumers’ motives and intention to purchase organic foods. Using the face-to-face survey approach, a total of 1,067 responses were collected from consumers in China. Data analysis was performed using a two-step structural equation modeling (SEM) approach, i.e., measurement and structural models. The findings indicated that both values influence the intention to purchase organic foods through the mediation of motives. Specifically, the altruistic value influences the environmental concern (EC), and the egoistic value influences the health concern (HC). Moreover, the perceived uncertainty negatively moderates a relationship between consumer HC and organic purchase intention while positively moderating a relationship between consumer EC and organic purchase intention. Several implications and suggestions are also discussed.
Pretensive Shared Reality: From Childhood Pretense to Adult Imaginative Play
Authors: Kapitany Rohan , Hampejs Tomas , Goldstein Thalia R.
Published: February 2022

Imaginative pretend play is often thought of as the domain of young children, yet adults regularly engage in elaborated, fantastical, social-mediated pretend play. We describe imaginative play in adults via the term “pretensive shared reality;” Shared Pretensive Reality describes the ability of a group of individuals to employ a range of higher-order cognitive functions to explicitly and implicitly share representations of a bounded fictional reality in predictable and coherent ways, such that this constructed reality may be explored and invented/embellished with shared intentionality in anad hocmanner. Pretensive Shared Reality facilitates multiple individual and social outcomes, including generating personal and group-level enjoyment or mirth, the creation or maintenance of social groups, or the safe exploration of individual self-concepts (such as alternative expression of a players sexual or gender identity). Importantly, Pretensive Shared Reality (both within the specific context of table-top role-playing games, and other instances) are primarily co-operative and co-creative. We draw on multiple examples, and focus on Table-Top Role Playing games (TTRPG) – and specifically, the most popular and enduring table-top role-playing games, Dungeons & Dragons (D&D) – as a primary example of such play. Our conception of “pretensive shared reality” links the widespread existence and forms of adult imaginative play to childhood pretense, places it within a developmental and evolutionary context, and argues that pretensive shared realities – which underpin many forms of imaginative culture – are an important topic of study unto themselves, and may be utilized to provide methodological insight into a variety of psychological domains.
Meaning of Education and Wellbeing: Understanding and Preventing the Risk of Loss of Meaning in Students
Authors: Baatouche Nadia , de Maricourt Paul , Bernaud Jean-Luc
Published: February 2022

The phenomenon of malaise is on the rise at universities, reflecting a deteriorating psychological state that is a combination of anxiety and stress factors. This psychological and emotional upheaval within students is indicative of a fundamental existential issue. In fact, hidden behind the choice of an educational program is the significance given by the student to their life goals. It is this dimension of attributing meaning to one’s education and, more broadly, to one’s life (the existential dimension) that we have sought to explore. We hypothesized that a stable investment in one’s life goals and a sense of psychological wellbeing during one’s studies could be fostered by reflective work done alongside the educational process. Our research took the form of a mixed methodological approach to the attribution of meaning to education, including an interpretive phenomenological analysis (IPA), and the experimentation of support for the meaning of education. Four dimensions of meaning were found to be observable in varying degrees in all students, each playing a specific role. Moreover, this research has confirmed that the meaning of studies is not to be understood solely in terms of education, but is part of a singular life story. Reflective work, developing meaning, facilitated by others (advisor, teacher, etc.) can help preserve/restore the feeling of wellbeing. It should be noted that, as the work presented in this article predates the pandemic, we will not address the amplifying effects of this health crisis on existential issues, which some recent studies are beginning to highlight.
“Aging Means to Me… That I Feel Lonely More Often”? An Experimental Study on the Effects of Age Simulation Regarding Views on Aging
Authors: Schmidt Laura I. , Schlomann Anna , Gerhardy Thomas , Wahl Hans-Werner
Published: February 2022

Over the last decades, educational programs involving age simulation suits (ASS) emerged with the ambition to further the understanding of age-related loss experiences, enhance empathy and reduce negative attitudes toward older adults in healthcare settings and in younger age groups at large. However, the impact of such “instant aging” interventions on individuals’ personal views on aging have not been studied yet. The aim of the current study is to address possible effects of ASS interventions on multiple outcomes related to views on aging, i.e., aging-related cognitions (i.e., expectations regarding social losses), awareness of age-related change (AARC) and age stereotypes. Moreover, we explore effects on broader constructs with relevance to aging, i.e., perceived obsolescence, risk perceptions, as well as desired support through technology. In a within-subjects design, N = 40 participants (M = 61.4 years, SD = 6.16) went through a series of established geriatric assessments (i.e., Timed up and Go) with and without an ASS. Views on aging constructs were assessed in standardized questionnaires before and after the ASS intervention. Changes in aging-related cognitions were observed, with more negative expectations regarding social integration and continuous development after wearing the ASS. AARC and age stereotypes did not change from pre- to post-assessment, but participants reported an increased susceptibility to age-associated impairments and stronger feelings of obsolescence. Those participants who exhibited higher difficulties in geriatric assessments while wearing the suit reported higher openness to be supported by intelligent assistive devices or robots afterwards. We conclude that ASS interventions should only be combined with education on losses and gains during the aging process to prevent negative effects on individual views on aging. On the other hand, potentials regarding technology acceptance and formation of intentions to engage in prevention and health behaviors among middle-aged to young-old adults are discussed.