bluuebunny/crossref_metadata_2025 huggingface dataset:
BIO-GATS: A Tool for Automated GPCR Template Selection Through a Biophysical Approach for Homology Modeling
Authors: Jabeen Amara , Vijayram Ramya , Ranganathan Shoba
Published: April 2021

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins with more than 800 members. GPCRs are involved in numerous physiological functions within the human body and are the target of more than 30% of the United States Food and Drug Administration (FDA) approved drugs. At present, over 400 experimental GPCR structures are available in the Protein Data Bank (PDB) representing 76 unique receptors. The absence of an experimental structure for the majority of GPCRs demand homology models for structure-based drug discovery workflows. The generation of good homology models requires appropriate templates. The commonly used methods for template selection are based on sequence identity. However, there exists low sequence identity among the GPCRs. Sequences with similar patterns of hydrophobic residues are often structural homologs, even with low sequence identity. Extending this, we propose a biophysical approach for template selection based principally on hydrophobicity correspondence between the target and the template. Our approach takes into consideration other relevant parameters, including resolution, similarity within the orthosteric binding pocket of GPCRs, and structure completeness, for template selection. The proposed method was implemented in the form of a free tool called Bio-GATS, to provide the user with easy selection of the appropriate template for a query GPCR sequence. Bio-GATS was successfully validated with recent published benchmarking datasets. An application to an olfactory receptor to select an appropriate template has also been provided as a case study.
Analysis of Hemichannels and Gap Junctions: Application and Extension of the Passive Transmembrane Ion Transport Model
Authors: Wang Qiqian , Liu Shenquan
Published: April 2021

Electrical synaptic transmission is an essential form of interneuronal communication which is mediated by gap junctions that permit ion flow. Three gene families (connexins, innexins, and pannexins) have evolved to form gap junctional channels. Each gap junctional channel is formed by the docking of the hemichannel of one cell with the corresponding hemichannel of an adjacent cell. To date, there has been a lack of study models to describe this structure in detail. In this study, we demonstrate that numerical simulations suggest that the passive transmembrane ion transport model, based on the generality of ion channels, also applies to hemichannels in non-junctional plasma membranes. On this basis, we established a gap junctional channel model, which describes hemichannels' docking. We simulated homotypic and heterotypic gap junctions formed by connexins, innexins, and pannexins. Based on the numerical results and our theoretical model, we discussed the physiology of hemichannels and gap junctions, including ion blockage of hemichannels, voltage gating of gap junctions, and asymmetry and delay of electrical synaptic transmission, for which the numerical simulations are first comprehensively realized.
Real-Time Simulation of a Cerebellar Scaffold Model on Graphics Processing Units
Authors: Kuriyama Rin , Casellato Claudia , D'Angelo Egidio , Yamazaki Tadashi
Published: April 2021

Large-scale simulation of detailed computational models of neuronal microcircuits plays a prominent role in reproducing and predicting the dynamics of the microcircuits. To reconstruct a microcircuit, one must choose neuron and synapse models, placements, connectivity, and numerical simulation methods according to anatomical and physiological constraints. For reconstruction and refinement, it is useful to be able to replace one module easily while leaving the others as they are. One way to achieve this is via a scaffolding approach, in which a simulation code is built on independent modules for placements, connections, and network simulations. Owing to the modularity of functions, this approach enables researchers to improve the performance of the entire simulation by simply replacing a problematic module with an improved one. Casali et al. (2019) developed a spiking network model of the cerebellar microcircuit using this approach, and while it reproduces electrophysiological properties of cerebellar neurons, it takes too much computational time. Here, we followed this scaffolding approach and replaced the simulation module with an accelerated version on graphics processing units (GPUs). Our cerebellar scaffold model ran roughly 100 times faster than the original version. In fact, our model is able to run faster than real time, with good weak and strong scaling properties. To demonstrate an application of real-time simulation, we implemented synaptic plasticity mechanisms at parallel fiber–Purkinje cell synapses, and carried out simulation of behavioral experiments known as gain adaptation of optokinetic response. We confirmed that the computer simulation reproduced experimental findings while being completed in real time. Actually, a computer simulation for 2 s of the biological time completed within 750 ms. These results suggest that the scaffolding approach is a promising concept for gradual development and refactoring of simulation codes for large-scale elaborate microcircuits. Moreover, a real-time version of the cerebellar scaffold model, which is enabled by parallel computing technology owing to GPUs, may be useful for large-scale simulations and engineering applications that require real-time signal processing and motor control.
Effects of Locomotion in Auditory Cortex Are Not Mediated by the VIP Network
Authors: Yavorska Iryna , Wehr Michael
Published: April 2021

Movement has a prominent impact on activity in sensory cortex, but has opposing effects on visual and auditory cortex. Both cortical areas feature a vasoactive intestinal peptide-expressing (VIP) disinhibitory circuit, which in visual cortex contributes to the effect of running. In auditory cortex, however, the role of VIP circuitry in running effects remains poorly understood. Running and optogenetic VIP activation are known to differentially modulate sound-evoked activity in auditory cortex, but it is unknown how these effects vary across cortical layers, and whether laminar differences in the roles of VIP circuitry could contribute to the substantial diversity that has been observed in the effects of both movement and VIP activation. Here we asked whether VIP neurons contribute to the effects of running, across the layers of auditory cortex. We found that both running and optogenetic activation of VIP neurons produced diverse changes in the firing rates of auditory cortical neurons, but with distinct effects on spontaneous and evoked activity and with different patterns across cortical layers. On average, running increased spontaneous firing rates but decreased evoked firing rates, resulting in a reduction of the neuronal encoding of sound. This reduction in sound encoding was observed in all cortical layers, but was most pronounced in layer 2/3. In contrast, VIP activation increased both spontaneous and evoked firing rates, and had no net population-wide effect on sound encoding, but strongly suppressed sound encoding in layer 4 narrow-spiking neurons. These results suggest that VIP activation and running act independently, which we then tested by comparing the arithmetic sum of the two effects measured separately to the actual combined effect of running and VIP activation, which were closely matched. We conclude that the effects of locomotion in auditory cortex are not mediated by the VIP network.
Small Vessel Disease Burden and Outcomes of Mechanical Thrombectomy in Ischemic Stroke: A Systematic Review and Meta-Analysis
Authors: Xu Tao , Wang You , Yuan Jinxian , Chen Yangmei , Luo Haiyan
Published: April 2021

Background: Cerebral small vessel disease (SVD) is prevalent in the population, especially among elderly individuals. Substantial uncertainties remain about the clinical relevance of SVD with outcomes of mechanical thrombectomy (MT) in acute ischemic stroke (AIS).

Objectives: This systematic review and meta-analysis was performed to evaluate the association between SVD and clinical outcomes in patients with AIS undergoing MT.

Methods: We systematically searched the Medline, Embase, and Cochrane databases for relevant clinical studies. The exposure of SVD mainly included leukoaraiosis, cerebral microbleeds (CMBs), and lacunes. The pooled OR was used to calculate the association between each subtype of SVD and outcomes of MT. The primary outcome was poor functional outcome, which was defined as a modified Rankin Scale score (mRS) ≥3 at 90 days after MT. The secondary outcomes included mortality at 90 days, in-hospital mortality, intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage (sICH), successful recanalization and futile recanalization (FR), early neurological improvement, and early neurological deterioration (END) after MT.

Results: Overall, 20 studies with 5,189 patients with AIS undergoing MT were included. High leukoaraiosis burden (HLB) at baseline was associated with increased risks of poor functional outcome at 90 days (OR 2.70, 95% CI 2.01–3.63; p < 0.001; 10 studies; n = 2,004), in-hospital mortality (OR 4.06, 95% CI 1.48–11.13; p = 0.006; 2 studies; n = 314), FR (OR 5.00, 95% CI 2.86–8.73; p < 0.001; 3 studies; n = 493), and END (OR 2.65, 95% CI 1.09–6.45; 1 study; n = 273) after MT. HLB (VSS 3–4 or FS ≥ 2) at baseline was not associated with mortality at 90 days, ICH, or sICH after MT. CMBs at baseline were found to be associated with increased risks of poor functional outcome at 90 days (OR 1.84, 95% CI 1.17–2.90; p = 0.008; 2 studies; n = 1,924) after MT. We found no association between the presence of lacunes and poor functional outcome at 90 days after MT.

Conclusions: In patients with AIS undergoing MT, HLB and CMBs were associated with increased risks of unfavorable outcomes after MT.
Clinical Features of Cluster Headache: A Hospital-Based Study in Taiwan
Authors: Ko Chien-An , Lin Guan-Yu , Ting Chi-Hsin , Sung Yueh-Feng , Lee Jiunn-Tay , Tsai Chia-Kuang , Tsai Chia-Lin , Lin Yu-Kai , Ho Tsung-Han , Yang Fu-Chi
Published: April 2021

Most previous studies on cluster headache (CH) focus on Western populations. This study aimed to investigate the clinical characteristics of CH in a neurology outpatient population in Taiwan. A cross-sectional survey was conducted from July 2015 to June 2019 in a medical college affiliated with a tertiary care hospital (Tri-Service General Hospital) in Taiwan. All consecutive patients reporting headache as their chief complaint were asked to participate in a face-to-face interview with a qualified headache specialist and to complete a detailed self-administered questionnaire. The diagnosis of CH was made according to the Third edition of the International Classification of Headache Disorders. The subjects comprised 80 consecutive new CH patients (13 women and 67 men; ratio, 1:5). The mean age at presentation was 36.0 ± 10.8 years (range, 16–64 years), mean age at onset was 27.2 ± 12.1 years (range, 5–65 years), and mean time lag before diagnosis was 9.3 ± 10.5 years (range, 0–46.4 years). Of the total CH patients, 25.3% reported feelings of restlessness during headache episodes. A seasonal predilection was reported by 18% of the CH patients. The use of tobacco was the most common (44/80 patients). Chronic CH was only observed in 5% of the patients and only one patient (1.3%) reported both a positive family history for CH and aura. Features of CH in Taiwanese patients differed from that of Caucasian patients; a lower prevalence of chronic CH, positive family history of CH, and occurrence of aura may be less common in the former than in the latter.
Increased Relative Delta Bandpower and Delta Indices Revealed by Continuous qEEG Monitoring in a Rat Model of Ischemia-Reperfusion
Authors: Ferreira Luan Oliveira , Mattos Bruna Gerrits , Jóia de Mello Vanessa , Martins-Filho Arnaldo Jorge , Costa Edmar Tavares da , Yamada Elizabeth Sumi , Hamoy Moisés , Lopes Dielly Catrina Favacho
Published: April 2021

The present study describes the electroencephalographic changes that occur during cerebral ischemia and reperfusion in animals submitted to transient focal cerebral ischemia by middle cerebral artery occlusion (MCAO) for 30 min. For this, male Wistar rats were divided into two groups (n = 6 animals/group): (1) sham (control) group, and (2) ischemic/reperfusion group. The quantitative electroencephalography (qEEG) was recorded during the ischemic and immediate reperfusion (acute) phases, and then once a day for 7 days after the MCAO (subacute phase). The acute phase was characterized by a marked increase in the relative delta wave band power (p < 0.001), with a smaller, but significant increase in the relative alpha wave bandpower in the ischemic stroke phase, in comparison with the control group (p = 0.0054). In the immediate reperfusion phase, however, there was an increase in the theta, alpha, and beta waves bandpower (p < 0.001), but no alteration in the delta waves (p = 0.9984), in comparison with the control group. We also observed high values in the delta/theta ratio (DTR), the delta/alpha ratio (DAR), and the (delta+theta)/(alpha+beta) ratio (DTABR) indices during the ischemia (p < 0.05), with a major reduction in the reperfusion phase. In the subacute phase, the activity of all the waves was lower than that of the control group (p < 0.05), although the DTR, DAR, and DTABR indices remained relatively high. In conclusion, early and accurate identification of decreased delta wave bandpower, DTR, DAR, and DTABR indices, and an increase in the activity of other waves in the immediate reperfusion phase may represent an important advance for the recognition of the effectiveness of reperfusion therapy.
Reflexive and Intentional Saccadic Eye Movements in Migraineurs
Authors: Filippopulos Filipp M. , Goeschy Christine , Schoeberl Florian , Eren Ozan E. , Straube Andreas , Eggert Thomas
Published: April 2021

Background: Migraine has been postulated to lead to structural and functional changes of different cortical and subcortical areas, including the frontal lobe, the brainstem, and cerebellum. The (sub-)clinical impact of these changes is a matter of debate. The spectrum of possible clinical differences include domains such as cognition but also coordination. The present study investigated the oculomotor performance of patients with migraine with and without aura compared to control subjects without migraine in reflexive saccades, but also in intentional saccades, which involve cerebellar as well as cortical networks.

Methods: In 18 patients with migraine with aura and 21 patients with migraine without aura saccadic eye movements were recorded in two reflexive (gap, overlap) and two intentional (anti, memory) paradigms and compared to 25 controls without migraine.

Results: The main finding of the study was an increase of saccade latency in patients with and without aura compared to the control group solely in the anti-task. No deficits were found in the execution of reflexive saccades.

Conclusions: Our results suggest a specific deficit in the generation of correct anti-saccades, such as vector inversion. Such processes are considered to need cortical networks to be executed correctly. The parietal cortex has been suggested to be involved in vector inversion processes but is not commonly described to be altered in migraine patients. It could be discussed that the cerebellum, which is recently thought to be involved in the pathophysiology of migraine, might be involved in distinct processes such as spatial re-mapping through known interconnections with parietal and frontal cortical areas.
RYR2 Mutations Are Associated With Benign Epilepsy of Childhood With Centrotemporal Spikes With or Without Arrhythmia
Authors: Ma Mei-Gang , Liu Xiao-Rong , Wu Yuan , Wang Jie , Li Bing-Mei , Shi Yi-Wu , Su Tao , Li Bin , Liu De-Tian , Yi Yong-Hong , Liao Wei-Ping
Published: April 2021

RYR2 encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the RYR2 mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between RYR2 gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. RYR2 mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs∗6), two heterozygous missense mutations (c.2353G > A/p.Asp785Asn and c.8574G > A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A > G/p.Asn1551Ser and c.11693T > C/p.Ile3898Thr, c.7469T > C/p.Val2490Ala and c.12770G > A/p.Arg4257Gln, respectively). Asp785Asn was a de novo missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between RYR2 variants and epilepsy. This study suggests that RYR2 gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with RYR2 mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.
ABCA7 Regulates Brain Fatty Acid Metabolism During LPS-Induced Acute Inflammation
Authors: Aikawa Tomonori , Ren Yingxue , Holm Marie-Louise , Asmann Yan W. , Alam Amer , Fitzgerald Michael L. , Bu Guojun , Kanekiyo Takahisa
Published: April 2021

The ATP binding cassette subfamily A member 7 (ABCA7) gene is one of the significant susceptibility loci for Alzheimer’s disease (AD). Furthermore, ABCA7 loss of function variants resulting from premature termination codon in the gene are associated with increased risk for AD. ABCA7 belongs to the ABC transporter family, which mediates the transport of diverse metabolites across the cell membrane. ABCA7 is also involved in modulating immune responses. Because the immune system and lipid metabolism causatively engage in the pathogenesis of AD, we investigated how ABCA7 haplodeficiency modulates the metabolic profile in mouse brains during acute immune response using a metabolomics approach through LC/Q-TOF-MS. Peripheral lipopolysaccharide (LPS) stimulation substantially influenced the metabolite content in the cortex, however, the effect on metabolic profiles in Abca7 heterozygous knockout mice (Abca7±) was modest compared to that in the control wild-type mice. Weighted gene co-expression network analysis (WGCNA) of the metabolomics dataset identified two modules influenced by LPS administration and ABCA7 haplodeficiency, in which glycerophospholipid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism were identified as major pathways. Consistent with these findings, we also found that LPS stimulation increased the brain levels of eicosapentaenoic acid, oleic acid, and palmitic acid in Abca7± mice, but not control mice. Together, our results indicate that ABCA7 is involved in the crosstalk between fatty acid metabolism and inflammation in the brain, and disturbances in these pathways may contribute to the risk for AD.
Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence
Authors: Penkert Judith , Märtens Andre , Seifert Martin , Auber Bernd , Derlin Katja , Hille-Betz Ursula , Hörmann Philipp , Klopp Norman , Prokein Jana , Schlicker Lisa , Wacker Frank , Wallaschek Hannah , Schlegelberger Brigitte , Hiller Karsten , Ripperger Tim , Illig Thomas
Published: April 2021

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.
Clinical Characteristics and Factors Associated With Hypertension in 205 Hospitalized Children: A Single-Center Study in Southwest China
Authors: Yang Zhiyong , Huang Yanyun , Qin Yan , Pang Yusheng
Published: April 2021

Objective: The aim of this study was to investigate the clinical characteristics and factors associated with pediatric hypertension and target organ damage (TOD).

Methods: We retrospectively reviewed clinical data from 205 children with hypertension treated in our hospital from 2007 to 2018. The patients were classified based on the type of hypertension (primary, secondary) and presence of TOD (heart, brain, retina). Logistic regression analysis was performed to identify the factors independently associated with hypertension and TOD.

Results: There were 107 males, 97 females, and one intersex in this study, with an age range of 0.1–17.9 years. Majority of cases (177, 86.3%) had secondary hypertension, while 13.7% had primary hypertension. The most frequent cause of secondary hypertension was renal disease (59.32%). Elevated serum creatinine level (odds ratio [OR] = 7.22, 95% confidence interval [95% CI] = 1.6–32.62, P = 0.01), blood urea nitrogen (OR = 6.33, 95% CI = 1.81–22.19, P = 0.004), serum uric acid level (OR = 3.66, 95% CI = 1.20–11.22, P = 0.023), and albuminuria (OR = 3.72, 95% CI = 1.50–9.26, P = 0.005) were independently associated with secondary hypertension. Elevated serum uric acid and blood urea nitrogen levels were associated with left ventricular hypertrophy (OR = 6.638, 95% CI = 1.349–32.657, P = 0.02) and hypertensive encephalopathy (OR = 4.384, 95% CI = 1.148–16.746, P = 0.031), respectively. Triglyceride level correlated with hypertensive retinopathy (P = 0.001).

Conclusion: Pediatric hypertension was most often secondary, with renal disease as the leading cause. Elevated levels of serum uric acid, blood urea nitrogen, serum creatinine, and albuminuria may indicate secondary hypertension in childhood. Elevated serum uric acid, blood urea nitrogen, and triglyceride levels were associated with left ventricular hypertrophy, hypertensive encephalopathy, and hypertensive retinopathy, respectively.
Network Pharmacology for Analyzing the Key Targets and Potential Mechanism of Wogonin in Gliomas
Authors: Wang Zaizhong , Cheng Lulu , Shang Zhigang , Li Zhihui , Zhao Yuping , Jin Wenwen , Li Yingyue , Su Fangchu , Mao Xiaobo , Chen Chuanliang , Zhang Jianhua
Published: April 2021

Objective: To analyze the key targets and potential mechanisms underlying the volatile components of Scutellaria baicalensis Georgi acting on gliomas through network pharmacology combined with biological experiments.

Methods: We have extracted the volatile components of Scutellaria baicalensis by gas chromatography-mass spectrometry (GC-MS) and determined the active components related to the onset and development of gliomas by combining the results with the data from the Traditional Chinese Medicine Systems Pharmacology database. We screened the same targets for the extracted active components and gliomas through network pharmacology and then constructed a protein-protein interaction network. Using a Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we analyzed the protein effects and regulatory pathways of the common targets. Lastly, we employed ELISA and Western blot in verifying the key targets in the regulatory pathway.

Results: We ultimately determined that the active component in S. baicalensis Georgi related to the onset and development of gliomas was Wogonin. The results of the network pharmacology revealed 85 targets for glioma and Wogonin. We used gene ontology to analyze these target genes and found that they involved 30 functions, such as phosphatidylinositol phosphokinase activation, while the KEGG analysis showed that there were 10 regulatory pathways involved. Through the following analysis, we found that most of the key target genes are distributed in the PI3K-Akt and interleukin 17 signaling pathways. We then cultured U251 glioma cells for the experiments. Compared with the control group, no significant change was noted in the caspase-3 expression; however, cleaved caspase-3 expression increased significantly and was dose-dependent on Wogonin. The expression of Bad and Bcl-2 with 25 μM of Wogonin has remained unchanged, but when the Wogonin dose was increased to 100 μM, the expression of Bad and Bcl-2 was noted to change significantly (Bad was significantly upregulated, while Bcl-2 was significantly downregulated) and was dose-dependent on Wogonin. The ELISA results showed that, compared with the control group, the secretion of tumor necrosis factor alpha, IL-1β, and IL-6 decreased as the Wogonin concentration increased. Tumor necrosis factor alpha downregulation had no significant dose-dependent effect on Wogonin, the inhibitory effect of 25 μM of Wogonin on IL-6 was not significant, and IL-1β downregulation had a significant dose-dependent effect on Wogonin.

Conclusion: Wogonin might promote the apoptosis of glioma cells by upregulating proapoptotic factors, downregulating antiapoptotic factors, and inhibiting the inflammatory response, thereby inhibiting glioma progression.
Exercise-Induced Modulation of Angiotensin II Responses in Femoral Veins From 2-Kidney-1-Clip Hypertensive Rats
Authors: Chies Agnaldo Bruno , Spadella Maria Angélica , de Oliveira Priscila Ramos , Domeniconi Raquel Fantin , de Mello Santos Talita , Moreira Roseli Peres , Rosales Carla B. , Casarini Dulce Elena , Navar Luis Gabriel
Published: April 2021

The present study investigated the angiotensin II (Ang II) responses in rat femoral veins taken from 2-kidney-1clip (2K1C) hypertensive rats at 4 weeks after clipping, as well as the effects of exercise on these responses. In this manner, femoral veins taken from 2K1C rats kept at rest or exposed to acute exercise or to exercise training were challenged with Ang II or endothelin-1 (ET-1) in organ bath. Simultaneously, the presence of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were determined in these preparations by western blotting. In these experiments, femoral veins exhibited subdued Ang II responses. However, after nitric oxide (NO) synthesis blockade, the responses were higher in the femoral veins taken from animals kept at rest [0.137(0.049–0.245);n= 10] than those obtained in trained animals kept at rest [0.008(0.001–0.041);n= 10] or studied after a single bout of exercise [0.001(0.001–0.054);n= 11]. In preparations in which, in addition to NO synthesis, both the local production of prostanoids and the action of ET-1 on type A (ETA) or B (ETB) receptors were inhibited, the differences induced by exercise were no longer observed. In addition, neither ET-1 responses nor the presence of COX-1 and COX-2 in these preparations were modified by the employed exercise protocols. In conclusion, NO maintains Ang II responses reduced in femoral veins of 2K1C animals at rest. However, vasodilator prostanoids as well as other relaxing mechanisms, activated by ETBstimulation, are mobilized by exercise to cooperate with NO in order to maintain controlled Ang II responses in femoral veins.
The Regulation of Adaptation to Cold and Drought Stresses in Poa crymophila Keng Revealed by Integrative Transcriptomics and Metabolomics Analysis
Authors: Wang Yan , Li Xin-Yu , Li Cai-Xia , He Yuan , Hou Xin-Yi , Ma Xin-Rong
Published: April 2021

Poa crymophila Keng is highly adaptable to long-term low temperature and drought conditions, making it a desirable foraging grass of the Qinghai-Tibet Plateau. Here, the widely targeted metabolomics and comparative transcriptome analyses were utilized for the discovery of metabolites and genes in P. crymophila in response to cold and drought stresses. P. crymophila were exposed to −5°C for 24 h and recovered to 22°C for 48 h, as well as drought for 10 days followed by re-watering for 1 day. In total, 779 metabolic features were assigned to metabolites and 167,845 unigenes were generated. Seventeen compounds showed significant up-regulation (variable importance in project >1) under both stresses in the metabolic profiling, mainly annotated as carbohydrates, flavones, and phenylpropanoids. The genes which were positively correlated with these metabolites were assigned to pathways (sucrose-starch, raffinose, phenylpropanoid, and flavone metabolism) using the Mapman software package. Alpha-amylase, beta-fructofuranosidase, and sugar transport genes degraded the glucose and starch to small molecule sugars for the purpose of osmotic adjustment and to provide more energy for the growth of P. crymophila in an adverse environment. The induction of cinnamoyl-CoA reductase (CCR) and the MYB gene as well as the sharp increase in schizandrin, a kind of lignan, showed that this likely has the closest connection with the tolerance to both stresses. Four significantly induced flavone compounds are probably involved in reducing oxidative damage. Our results indicated that activation of the phenlypropanoid pathway plays the primary role in P. crymophila adapting to harsh environments. This study showed the mechanism of P. crymophila responding to both cold and drought stresses and showed the discovery of a new biological regulator against stresses.
Variation for Composition and Quality in a Collection of the Resilient Mediterranean ‘de penjar’ Long Shelf-Life Tomato Under High and Low N Fertilization Levels
Authors: Rosa-Martínez Elena , Adalid Ana M. , Alvarado Luis E. , Burguet Resurrección , García-Martínez María D. , Pereira-Dias Leandro , Casanova Cristina , Soler Elena , Figàs María R. , Plazas Mariola , Prohens Jaime , Soler Salvador
Published: April 2021

The ‘de penjar’ tomato (Solanum lycopersicum L.) is a group of local varieties from the Spanish Mediterranean region carrying the alc mutation, which provides long shelf-life. Their evolution under low-input management practices has led to the selection of resilient genotypes to adverse conditions. Here we present the first evaluation on nutritional fruit composition of a collection of 44 varieties of ‘de penjar’ tomato under two N fertilization levels, provided by doses of manure equivalent to 162 kg N ha–1 in the high N treatment and 49 kg N ha–1 in the low N treatment. Twenty-seven fruit composition and quality traits, as well as plant yield and SPAD value, were evaluated. A large variation was observed, with lycopene being the composition trait with the highest relative range of variation (over 4-fold) under both N treatments, and significant differences among varieties were detected for all traits. While yield and most quality traits were not affected by the reduction in N fertilization, fruits from the low N treatment had, on average, higher values for hue (5.9%) and lower for fructose (−11.5%), glucose (−15.8%), and total sweetness index (−12.9%). In addition, lycopene and β-carotene presented a strongly significant genotype × N input interaction. Local varieties had higher values than commercial varieties for traits related to the ratio of sweetness to acidity and for vitamin C, which reinforces the appreciation for their organoleptic and nutritional quality. Highest-yielding varieties under both conditions displayed wide variation in the composition and quality profiles, which may allow the selection of specific ideotypes with high quality under low N conditions. These results revealed the potential of ‘de penjar’ varieties as a genetic resource in breeding for low N inputs and improving the organoleptic and nutritional tomato fruit quality.
FASCICLIN-LIKE 18 Is a New Player Regulating Root Elongation in Arabidopsis thaliana
Authors: Allelign Ashagre Hewot , Zaltzman David , Idan-Molakandov Anat , Romano Hila , Tzfadia Oren , Harpaz-Saad Smadar
Published: April 2021

The plasticity of root development represents a key trait that enables plants to adapt to diverse environmental cues. The pattern of cell wall deposition, alongside other parameters, affects the extent, and direction of root growth. In this study, we report that FASCICLIN-LIKE ARABINOGALACTAN PROTEIN 18 (FLA18) plays a role during root elongation inArabidopsis thaliana. Using root-specific co-expression analysis, we identifiedFLA18to be co-expressed with a sub-set of genes required for root elongation.FLA18encodes for a putative extra-cellular arabinogalactan protein from theFLA-gene family. Two independent T-DNA insertion lines, namedfla18-1andfla18-2, display short and swollen lateral roots (LRs) when grown on sensitizing condition of high-sucrose containing medium. Unlikefla4/salt overly sensitive 5(sos5), previously shown to display short and swollen primary root (PR) and LRs under these conditions, the PR of thefla18mutants is slightly longer compared to the wild-type. Overexpression of theFLA18CDS complemented thefla18root phenotype. Genetic interaction between either of thefla18alleles andsos5reveals a more severe perturbation of anisotropic growth in both PR and LRs, as compared to the single mutants and the wild-type under restrictive conditions of high sucrose or high-salt containing medium. Additionally, under salt-stress conditions,fla18sos5had a small, chlorotic shoot phenotype, that was not observed in any of the single mutants or the wild type. As previously shown forsos5, thefla18-1andfla18-1sos5root-elongation phenotype is suppressed by abscisic acid (ABA) and display hypersensitivity to the ABA synthesis inhibitor, Fluridon. Last, similar to other cell wall mutants,fla18root elongation is hypersensitive to the cellulose synthase inhibitor, Isoxaben. Altogether, the presented data assign a new role for FLA18 in the regulation of root elongation. Future studies of the unique vs. redundant roles of FLA proteins during root elongation is anticipated to shed a new light on the regulation of root architecture during plant adaptation to different growth conditions.
Efficient Transient Expression of Recombinant Proteins Using DNA Viral Vectors in Freshwater Microalgal Species
Authors: Malla Ashwini , Rosales-Mendoza Sergio , Phoolcharoen Waranyoo , Vimolmangkang Sornkanok
Published: April 2021

The increase in the world population, the advent of new infections and health issues, and the scarcity of natural biological products have spotlighted the importance of recombinant protein technology and its large-scale production in a cost-effective manner. Microalgae have become a significant promising platform with the potential to meet the increasing demand for recombinant proteins and other biologicals. Microalgae are safe organisms that can grow rapidly and are easily cultivated with basic nutrient requirements. Although continuous efforts have led to considerable progress in the algae genetic engineering field, there are still many hurdles to overcome before these microorganisms emerge as a mature expression system. Hence, there is a need to develop efficient expression approaches to exploit microalgae for the production of recombinant proteins at convenient yields. This study aimed to test the ability of the DNA geminiviral vector with Rep-mediated replication to transiently express recombinant proteins in the freshwater microalgal species Chlamydomonas reinhardtii and Chlorella vulgaris using Agrobacterium-mediated transformation. The SARS-CoV-2 receptor binding domain (RBD) and basic fibroblast growth factor (bFGF) are representative antigen proteins and growth factor proteins, respectively, that were subcloned in a geminiviral vector and were used for nuclear transformation to transiently express these proteins in C. reinhardtii and C. vulgaris. The results showed that the geminiviral vector allowed the expression of both recombinant proteins in both algal species, with yields at 48 h posttransformation of up to 1.14 μg/g RBD and 1.61 ng/g FGF in C. vulgaris and 1.61 μg/g RBD and 1.025 ng/g FGF in C. reinhardtii. Thus, this study provides a proof of concept for the use of DNA viral vectors for the simple, rapid, and efficient production of recombinant proteins that repress the difficulties faced in the genetic transformation of these unicellular green microalgae. This concept opens an avenue to explore and optimize green microalgae as an ideal economically valuable platform for the production of therapeutic and industrially relevant recombinant proteins in shorter time periods with significant yields.
Resistance of Winter Spelt Wheat [Triticum aestivum subsp. spelta (L.) Thell.] to Fusarium Head Blight
Authors: Chrpová Jana , Grausgruber Heinrich , Weyermann Verena , Buerstmayr Maria , Palicová Jana , Kozová Jana , Trávníčková Martina , Nguyen Quynh Trang , Moreno Amores Jose Esteban , Buerstmayr Hermann , Janovská Dagmar
Published: April 2021

Resistance to Fusarium head blight (FHB) of spelt wheat was investigated in field trials carried out at three European locations between 2016 and 2018. Resistance was assessed after artificial inoculation by visual scoring of symptoms and the determination of the contamination of grains and glumes with the mycotoxin deoxynivalenol (DON). It was found that typical spelt traits such as tall plant height, lax spikes, and tough glumes play a role as passive resistance factors. Across all test environments, modern spelt varieties with a significantly reduced plant height showed a significantly higher susceptibility to FHB and a higher contamination of the grains with DON compared to old landraces/varieties and plant genetic resources. Similarly, the lowest mycotoxin levels in grains were found only in old landraces and varieties, while the highest DON concentration was observed mainly in modern varieties. The results obtained can be used for the selection of suitable parental material for breeding spelt with improved FHB resistance.
Social Defeat, Psychotic Symptoms, and Crime in Young Caribbean Immigrants to Rotterdam
Authors: Vinkers David J. , Van de Vorst Micha , Hoek Hans W. , Van Os Jim
Published: April 2021

Background:The negative experience of being excluded from the majority group (social defeat) may be associated with psychosis in immigrants. The social defeat hypothesis is supported by the high frequency of perceived discrimination and acculturation problems in psychotic immigrants. In addition, social defeat may lead to crime through social problems such as unemployment, school dropout, a broken family structure, or psychotic symptoms.

Methods:We assessed the association between social defeat and acculturation on the one hand and broadly defined psychotic symptoms and crime on the other in Caribbean immigrants to Rotterdam who are aged 18–24 years. The municipality of Rotterdam provided data about Caribbean immigrants to Rotterdam. Acculturation, social defeat (perceived discrimination, sense of control, and evaluation of self and others), psychotic symptoms, and crime were assessed using online questionnaires.

Results:Social defeat was associated with psychotic symptoms in women (β = 0.614,p< 0.001). This relation applied particularly to the negative self-perception domain of social defeat. Acculturation was associated with neither social defeat nor psychotic symptoms or crime and did not mediate the association between social defeat and psychosis.

Conclusion:The social defeat hypothesis of psychosis may be gender-specific valid but does not extend to crime.
Computerized-Adaptive vs. Traditional Ratings of Depression and Suicidal Thoughts: An Assay Sensitivity Pilot Study in a Ketamine Clinical Trial
Authors: Grunebaum Michael F. , Mann J. John , Galfalvy Hanga C. , Gibbons Robert D.
Published: April 2021

There is a public health need for improved suicide risk assessment tools. This pilot methodology study compared the assay sensitivity of computerized adaptive tests (CAT) of depression and suicidal ideation vs. traditional ratings in a randomized trial subgroup. The last 20 persons to enroll in a published ketamine trial in suicidal depression were studied. This subgroup received traditional and CAT ratings at baseline, 24 h post-infusion and follow-up week 2, 4, and 6: Hamilton Depression Rating Scale, Beck Depression Inventory, and Beck Scale for Suicidal Ideation vs. the CAT-Depression Inventory and CAT-Suicide Scale. Results showed larger effect sizes (ES) for CAT compared with traditional clinician-rated and self-report scales. Coefficients of variation for baseline measurements were lower for CAT compared with traditional scales. This is the first study to show that CAT may have greater assay sensitivity for treatment effects, particularly for suicidal ideation, compared with traditional clinician-rated and non-adaptive self-rated scales in a randomized trial. The findings suggest CAT can enable quick long-term follow-up assessments via cellphone, tablet, or computer while minimizing response bias due to repeated measurement of the same symptom items.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01700829.
Participants' Comprehension of the Informed Consent in an Epidemiological Study on Dementia Prevalence: A Qualitative Study
Authors: Falvo Ilaria , Fiordelli Maddalena , Amati Rebecca , Ibnidris Aliaa , Albanese Emiliano , Fadda Marta
Published: April 2021

Aim:In the absence of an effective treatment, informed participation in dementia research can hardly be underestimated. However, although informed consent is key in biomedical research, it may become a barrier to participation. Whether informed consent may cause confusion and contribute to unfair participant selection in dementia research is not known. In preparation of a future epidemiological study on the prevalence and impact of dementia in Switzerland, we aimed to conduct a qualitative study to explore participants' comprehension of the purpose of informed consent form and process shortly after participation in the pilot and validation study that preceded the large scale survey.

Methods:We conducted a qualitative study with 22 participants of the validation phase of an epidemiological study on the prevalence and impact of dementia in Switzerland to capture their understanding of both the nature and the content of the informed consent form and process. Participants were older adults (65 years or more) eligible for a dementia epidemiological study and their informant (a person who could provide information on their health and cognition). None of the participants reported to be suffering from dementia at the time of the interview.

Results:We found that participants held inaccurate and potentially trust-threatening beliefs regarding the scope of the informed consent. Participants identified contradictory contextual, formal and content needs that are difficult to be fulfilled, and misperceived the clinical and research settings in terms of informed consent procedures.

Conclusions:Participants and their proxies should be informed about both the scope of the informed consent process, and the content of the informed consent document in a focused, age-appropriate manner, while dispelling confusion about the purpose of research.
Measuring Hypertension Progression With Transition Probabilities: Estimates From the WHO SAGE Longitudinal Study
Authors: Boateng Godfred O. , Lartey Stella T. , Baiden Philip , Si Lei , Biritwum Richard Berko , Kowal Paul , Magnussen Costan G. , Ben Taleb Ziyad , Palmer Andrew J. , Luginaah Isaac
Published: April 2021

This paper assessed the transition probabilities between the stages of hypertension severity and the length of time an individual might spend at a particular disease state using the new American College of Cardiology/American Heart Association hypertension blood pressure guidelines. Data for this study were drawn from the Ghana WHO SAGE longitudinal study, with an analytical sample of 1884 across two waves. Using a multistate Markov model, we estimated a seven-year transition probability between normal/elevated blood pressure (systolic ≤ 129 mm Hg & diastolic <80 mm Hg), stage 1 (systolic 130-139 mm Hg & diastolic 80-89 mm Hg), and stage 2 (systolic ≥140mm Hg & diastolic≥90 mm Hg) hypertension and adjusted for the individual effects of anthropometric, lifestyle, and socio-demographic factors. At baseline, 22.5% had stage 1 hypertension and 52.2% had stage 2 hypertension. The estimated seven-year transition probability for the general population was 19.0% (95% CI: 16.4, 21.8) from normal/elevated blood pressure to stage 1 hypertension, 31.6% (95% CI: 27.6, 35.4%) from stage 1 hypertension to stage 2 hypertension, and 48.5% (45.6, 52.1%) for remaining at stage 2. Other factors such as being overweight, obese, female, aged 60+ years, urban residence, low education and high income were associated with an increased probability of remaining at stage 2 hypertension. However, consumption of recommended servings of fruits and vegetables per day was associated with a delay in the onset of stage 1 hypertension and a recovery to normal/elevated blood pressure. This is the first study to show estimated transition probabilities between the stages of hypertension severity across the lifespan in sub-Saharan Africa. The results are important for understanding progression through hypertension severity and can be used in simulating cost-effective models to evaluate policies and the burden of future healthcare.