bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence and Germination of the Probiotic Bacillus subtilis DE111® in the Human Small Intestinal Tract: A Randomized, Crossover, Double-Blind, and Placebo-Controlled Study
Authors: Colom Joan , Freitas Daniela , Simon Annie , Brodkorb Andre , Buckley Martin , Deaton John , Winger Alison M.
Published: August 2021

Spore-based probiotics offer important advantages over other probiotics as they can survive the harsh gastric conditions of the stomach and bile salts in the small intestine, ultimately germinating in the digestive tract. A novel clinical trial in 11 ileostomy participants was conducted to directly investigate the presence and germination of the probiotic strain Bacillus subtilis DE111® in the small intestine. Three hours following ingestion of DE111®, B. subtilis spores (6.4 × 104 ± 1.3 × 105 CFU/g effluent dry weight) and vegetative cells (4.7 × 104 ± 1.1 × 105 CFU/g effluent dry weight) began to appear in the ileum effluent. Six hours after ingestion, spore concentration increased to 9.7 × 107 ± 8.1 × 107 CFU/g and remained constant to the final time point of 8 h. Vegetative cells reached a concentration of 7.3 × 107 ± 1.4 × 108 CFU/g at 7 h following ingestion. These results reveal orally ingested B. subtilis DE111® spores are able to remain viable during transit through the stomach and germinate in the small intestine of humans within 3 h of ingestion.
The Association of Metabolic Dysfunction and Mood Across Lifespan Interacts With the Default Mode Network Functional Connectivity
Authors: Portugal-Nunes Carlos , Reis Joana , Coelho Ana , Moreira Pedro Silva , Castanho Teresa Costa , Magalhães Ricardo , Marques Paulo , Soares José Miguel , Amorim Liliana , Cunha Pedro Guimarães , Santos Nadine Correia , Costa Patrício , Palha Joana Almeida , Sousa Nuno , Bessa João Miguel
Published: August 2021

Background: Numerous studies suggest a relationship between depression and metabolic syndrome, which is likely influenced by age. Interestingly, functional imaging analysis has shown an association between functional connectivity in the default mode network (DMN-FC) and components of metabolic syndrome, which is explored in this study.

Methods: From a larger longitudinal cohort study on healthy aging, 943 individuals were extensively characterized for mood and cognition. Among these, 120 individuals who were selected for displaying extreme cognitive performance within the normal range (good and poor performers) were further studied. Here, in a cross-sectional design, using confirmatory factor analysis (CFA), the association between metabolic dysfunction and depressive mood as a function of age and its relationship with DMN-FC was studied.

Results: Metabolic dysfunction was modeled as a second-order latent variable using CFA. First-order latent variables were obesity, glucose dysmetabolism, lipids imbalance, and blood pressure. Using multiple linear regression models, this study observed that metabolic dysfunction, glucose dysmetabolism, and lipids imbalance were linearly associated with depressive mood, and the association with obesity was U-shaped. The association of metabolic dysfunction, obesity, and glucose dysmetabolism with depressive mood is positive for the younger individuals in our sample and vanishes with aging. The FC of the right superior temporal gyrus with the DMN correlated with both obesity and depressive mood. In participants with higher obesity scores, FC increased with higher GDS scores, while in those with lower GDS scores, FC decreased. Age and blood pressure were associated with a more complex pattern of association between FC of the right supramarginal gyrus and GDS score.

Conclusion: The association of metabolic dysfunction with depressive mood is influenced by age and relates with differential patterns of DMN-FC. The combination of the effects of age, mood, and metabolic dysfunction is likely to explain the heterogeneity of DMN-FC, which deserves further investigation with larger and longitudinal studies.
Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-β Load
Authors: Schwarz Claudia , Lange Catharina , Benson Gloria S. , Horn Nora , Wurdack Katharina , Lukas Mathias , Buchert Ralph , Wirth Miranka , Flöel Agnes
Published: August 2021

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-β) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-β load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-β, as well as regional amyloid-β load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-β load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-β load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-β load in the parietal cortex. Higher levels of worry were associated with higher amyloid-β load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-β burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.
Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype
Authors: Yanai Shuichi , Endo Shogo
Published: August 2021

Aging is characterized generally by progressive and overall physiological decline of functions and is observed in all animals. A long line of evidence has established the laboratory mouse as the prime model of human aging. However, relatively little is known about the detailed behavioral and functional changes that occur across their lifespan, and how this maps onto the phenotype of human aging. To better understand age-related changes across the life-span, we characterized functional aging in male C57BL/6J mice of five different ages (3, 6, 12, 18, and 22 months of age) using a multi-domain behavioral test battery. Spatial memory and physical activities, including locomotor activity, gait velocity, and grip strength progressively declined with increasing age, although at different rates; anxiety-like behaviors increased with aging. Estimated age-related patterns showed that these functional alterations across ages are non-linear, and the patterns are unique for each behavioral trait. Physical function progressively declines, starting as early as 6 months of age in mice, while cognitive function begins to decline later, with considerable impairment present at 22 months of age. Importantly, functional aging of male C57BL/6J mouse starts at younger relative ages compared to when it starts in humans. Our study suggests that human-equivalent ages of mouse might be better determined on the basis of its functional capabilities.
Association Between Components of Cognitive Reserve and Serum BDNF in Healthy Older Adults
Authors: Collins Jessica M. , Hill Edward , Bindoff Aidan , King Anna E. , Alty Jane , Summers Mathew J. , Vickers James C.
Published: August 2021

Background: The brain-derived neurotrophic factor (BDNF) protein has been shown to have a prominent role in neuron survival, growth, and function in experimental models, and the BDNF Val66Met polymorphism which regulates its expression has been linked to resilience toward the effects of aging on cognition. Cognitively stimulating activity is linked to both increased levels of BDNF in the brain, and protection against age-related cognitive decline. The aim of this study was to investigate the associations between serum BDNF levels, the BDNF Val66Met genotype, and components of cognitive reserve in early and mid-life, measured with the Lifetime of Experiences Questionnaire (LEQ).

Methods: Serum BDNF levels were measured cross-sectionally in 156 participants from the Tasmanian Healthy Brain Project (THBP) cohort, a study examining the potential benefits of older adults engaging in a university-level education intervention. Multiple linear regression was used to estimate serum BDNF’s association with age, education, gender, BDNF Val66Met genotype, later-life university-level study, and cognitively stimulating activities measured by the LEQ.

Results: Serum BDNF in older adults was associated with early life education and training, increasing 0.007 log(pg/ml) [95%CI 0.001, 0.012] per unit on the LEQ subscale. Conversely, education and training in mid-life were associated with a −0.007 log(pg/ml) [−0.012, −0.001] decrease per unit on the LEQ subscale. Serum BDNF decreased with age (−0.008 log(pg/ml) [−0.015, −0.001] per year), and male gender (−0.109 log(pg/ml) [−0.203, −0.015]), but mean differences between the BDNF Val66Met polymorphisms were not significant (p = 0.066). All effect sizes were small, with mid-life education and training having the largest effect size (ηp2 = 0.044).

Conclusion: Education in both early and mid-life explained small but significant amounts of variance in serum BDNF levels, more than age or gender. These effects were opposed and independent, suggesting that education at different stages of life may be associated with different cognitive and neural demands. Education at different stages of life may be important covariates when estimating associations between other exposures and serum BDNF.
Functional Connectivity of the Anterior Nucleus of the Thalamus in Pediatric Focal Epilepsy
Authors: Piper Rory J. , Tangwiriyasakul Chayanin , Shamshiri Elhum A. , Centeno Maria , He Xiaosong , Richardson Mark P. , Tisdall Martin M. , Carmichael David W.
Published: August 2021

Objective: Whilst stimulation of the anterior nucleus of the thalamus has shown efficacy for reducing seizure frequency in adults, alterations in thalamic connectivity have not been explored in children. We tested the hypotheses that (a) the anterior thalamus has increased functional connectivity in children with focal epilepsy, and (b) this alteration in the connectome is a persistent effect of the disease rather than due to transient epileptiform activity.

Methods: Data from 35 children (7–18 years) with focal, drug-resistant epilepsy and 20 healthy children (7–17 years) were analyzed. All subjects underwent functional magnetic resonance imaging (fMRI) whilst resting and were simultaneously monitored with scalp electroencephalography (EEG). The fMRI timeseries were extracted for each Automated Anatomical Labeling brain region and thalamic subregion. Graph theory metrics [degree (DC) and eigenvector (EC) centrality] were used to summarize the connectivity profile of the ipsilateral thalamus, and its thalamic parcellations. The effect of interictal epileptiform discharges (IEDs) captured on EEG was used to determine their effect on DC and EC.

Results: DC was significantly higher in the anterior nucleus (p = 0.04) of the thalamus ipsilateral to the epileptogenic zone in children with epilepsy compared to controls. On exploratory analyses, we similarly found a higher DC in the lateral dorsal nucleus (p = 0.02), but not any other thalamic subregion. No differences in EC measures were found between patients and controls. We did not find any significant difference in DC or EC in any thalamic subregion when comparing the results of children with epilepsy before, and after the removal of the effects of IEDs.

Conclusions: Our data suggest that the anterior and lateral dorsal nuclei of the thalamus are more highly functionally connected in children with poorly controlled focal epilepsy. We did not detect a convincing change in thalamic connectivity caused by transient epileptiform activity, suggesting that it represents a persistent alteration to network dynamics.
Causes for Emergency Hospitalization of Neurological Patients With Palliative Care Needs
Authors: Willert Anna-Christin , Ploner Christoph J. , Kowski Alexander B.
Published: August 2021

Background: Acute and unexpected hospitalization can cause serious distress, particularly in patients with palliative care needs. Nevertheless, the majority of neurological inpatients receiving palliative care are admitted via an emergency department.

Objective: Identification of potentially avoidable causes leading to acute hospitalization of patients with neurological disorders or neurological symptoms requiring palliative care.

Methods: Retrospective analysis of medical records of all patients who were admitted via the emergency department and received palliative care in a neurological ward later on (n = 130).

Results: The main reasons for acute admission were epileptic seizures (22%), gait disorders (22%), disturbance of consciousness (20%), pain (17%), nutritional problems (17%), or paresis (14%). Possible therapy limitations, (non)existence of a patient decree, or healthcare proxy was documented in only 31%. Primary diagnoses were neoplastic (49%), neurodegenerative (30%), or cerebrovascular (18%) diseases. Fifty-nine percent were directly admitted to a neurological ward; 25% needed intensive care. On average, it took 24 h until the palliative care team was involved. In contrast to initially documented problems, key challenges identified by palliative care assessment were psychosocial problems. For 40% of all cases, a specialized palliative care could be organized.

Conclusion: Admissions were mainly triggered by acute events. Documentation of the palliative situation and treatment limitations may help to prevent unnecessary hospitalization. Although patients present with a complex symptom burden, emergency department assessment is not able to fully address multidimensionality, especially concerning psychosocial problems. Prospective investigations should develop short screening tools to identify palliative care needs of neurological patients already in the emergency department.
A Neuroprotective Locus Modulates Ischemic Stroke Infarction Independent of Collateral Vessel Anatomy
Authors: Lee Han Kyu , Wetzel-Strong Sarah E. , Aylor David L. , Marchuk Douglas A.
Published: August 2021

Although studies with inbred strains of mice have shown that infarct size is largely determined by the extent of collateral vessel connections between arteries in the brain that enable reperfusion of the ischemic territory, we have identified strain pairs that do not vary in this vascular phenotype, but which nonetheless exhibit large differences in infarct size. In this study we performed quantitative trait locus (QTL) mapping in mice from an intercross between two such strains, WSB/EiJ (WSB) and C57BL/6J (B6). This QTL mapping revealed only one neuroprotective locus on Chromosome 8 (Chr 8) that co-localizes with a neuroprotective locus we mapped previously from F2 progeny between C3H/HeJ (C3H) and B6. The allele-specific phenotypic effect on infarct volume at the genetic region identified by these two independent mappings was in the opposite direction of the parental strain phenotype; namely, the B6 allele conferred increased susceptibility to ischemic infarction. Through two reciprocal congenic mouse lines with either the C3H or B6 background at the Chr 8 locus, we verified the neuroprotective effects of this genetic region that modulates infarct volume without any effect on the collateral vasculature. Additionally, we surveyed non-synonymous coding SNPs and performed RNA-sequencing analysis to identify potential candidate genes within the genetic interval. Through these approaches, we suggest new genes for future mechanistic studies of infarction following ischemic stroke, which may represent novel gene/protein targets for therapeutic development.
Chronic Ethanol Exposure Enhances Facial Stimulation-Evoked Mossy Fiber–Granule Cell Synaptic Transmission via GluN2A Receptors in the Mouse Cerebellar Cortex
Authors: Li Bing-Xue , Dong Guang-Hui , Li Hao-Long , Zhang Jia-Song , Bing Yan-Hua , Chu Chun-Ping , Cui Song-Biao , Qiu De-Lai
Published: August 2021

Sensory information is transferred to the cerebellar cortex via the mossy fiber–granule cell (MF–GC) pathway, which participates in motor coordination and motor learning. We previously reported that chronic ethanol exposure from adolescence facilitated the sensory-evoked molecular layer interneuron–Purkinje cell synaptic transmission in adult mice in vivo. Herein, we investigated the effect of chronic ethanol exposure from adolescence on facial stimulation-evoked MF–GC synaptic transmission in the adult mouse cerebellar cortex using electrophysiological recording techniques and pharmacological methods. Chronic ethanol exposure from adolescence induced an enhancement of facial stimulation-evoked MF–GC synaptic transmission in the cerebellar cortex of adult mice. The application of an N-methyl-D-aspartate receptor (NMDAR) antagonist, D-APV (250 μM), induced stronger depression of facial stimulation-evoked MF–GC synaptic transmission in chronic ethanol-exposed mice compared with that in control mice. Chronic ethanol exposure-induced facilitation of facial stimulation evoked by MF–GC synaptic transmission was abolished by a selective GluN2A antagonist, PEAQX (10 μM), but was unaffected by the application of a selective GluN2B antagonist, TCN-237 (10 μM), or a type 1 metabotropic glutamate receptor blocker, JNJ16259685 (10 μM). These results indicate that chronic ethanol exposure from adolescence enhances facial stimulation-evoked MF–GC synaptic transmission via GluN2A, which suggests that chronic ethanol exposure from adolescence impairs the high-fidelity transmission capability of sensory information in the cerebellar cortex by enhancing the NMDAR-mediated components of MF–GC synaptic transmission in adult mice in vivo.
Altered Serum Immunological and Biochemical Parameters and Microbiota Composition in Patients With AN During Realimentation
Authors: Roubalova Radka , Prochazkova Petra , Dvorak Jiri , Hill Martin , Papezova Hana , Kreisinger Jakub , Bulant Josef , Lambertova Alena , Holanova Petra , Bilej Martin , Tlaskalova-Hogenova Helena
Published: August 2021

Anorexia nervosa (AN) is a life-threatening psychiatric disorder with not well-described pathogenesis. Besides the genetic and sociological factors, autoimmunity is also considered to take part in AN pathogenesis. We evaluated general serological factors showing the physiological state of 59 patients with AN at hospital admission and their discharge. We detected the altered levels of some general biochemical and immunological parameters. We also detected decreased levels of appetite-regulating alpha-melanocyte stimulating hormone (α-MSH) in patients at hospital admission. Moreover, elevated anti-α-MSH IgM levels and decreased anti-α-MSH IgA levels were observed in patients with AN. Therefore, we analyzed the gut microbiota composition with special focus on α-MSH antigen-mimetic containing microbes from the Enterobacteriaceae family. We correlated gut bacterial composition with anti-α-MSH Ig levels and detected decreasing IgG levels with increasing alpha diversity. The upregulation of pro-inflammatory cytokines IL-6, IL-17, and TNF-α were detected in patients with AN both prior and after hospitalization. We also evaluated the treatment outcome and improvement was observed in the majority of patients with AN. We provide new data about various serum biochemical parameters and their changes during the patients' hospitalization, with emphasis on the immune system, and its possible participation in AN pathogenesis.
Integrated Analysis of a Competing Endogenous RNA Network Reveals a Prognostic lncRNA Signature in Bladder Cancer
Authors: Peng Mou , Cheng Xu , Xiong Wei , Yi Lu , Wang Yinhuai
Published: August 2021

Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) to regulate mRNA expression through sponging microRNA in tumorigenesis and progression. However, following the discovery of new RNA interaction, the differentially expressed RNAs and ceRNA regulatory network are required to update. Our study comprehensively analyzed the differentially expressed RNA and corresponding ceRNA network and thus constructed a potentially predictive tool for prognosis. “DESeq2” was used to perform differential expression analysis. Two hundred and six differentially expressed (DE) lncRNAs, 222 DE miRNAs, and 2,463 DE mRNAs were found in this study. The lncRNA-mRNA interactions in the miRcode database and the miRNA-mRNA interactions in the starBase, miRcode, and mirTarBase databases were searched, and a competing endogenous RNA (ceRNA) network with 186 nodes and 836 interactions was subsequently constructed. Aberrant expression patterns of lncRNA NR2F1-AS1 and lncRNA AC010168.2 were evaluated in two datasets (GSE89006, GSE31684), and real-time polymerase chain reaction was also performed to validate the expression pattern. Furthermore, we found that these two lncRNAs were independent prognostic biomarkers to generate a prognostic lncRNA signature by univariate and multivariate Cox analyses. According to the lncRNA signature, patients in the high-risk group were associated with a poor prognosis and validated by an external dataset. A novel genomic-clinicopathologic nomogram to improve prognosis prediction of bladder cancer was further plotted and calibrated. Our study deepens the understanding of the regulatory ceRNA network and provides an easy-to-do genomic-clinicopathological nomogram to predict the prognosis in patients with bladder cancer.
Establishing a Provincial Registry for Recurrent Prostate Cancer: Providing Access to PSMA PET/CT in Ontario, Canada
Authors: Young Sympascho , Metser Ur , Sistani Golmehr , Langer Deanna L. , Bauman Glenn
Published: August 2021

Prostate Specific Membrane Antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is becoming established as a standard of care for the (re)staging of high-risk primary and prostate cancer recurrence after primary therapy. Despite the favorable performance of this imaging modality with high accuracy in disease detection, the availability of PSMA PET/CT varies across jurisdictions worldwide due to variability in the selection of PSMA PET/CT agent, regulatory approvals and funding. In Canada, PSMA based radiopharmaceuticals are still considered investigational new drug (IND), creating limitations in the deployment of these promising imaging agents. While regulatory approval rests with Health Canada, as a single payer health system, funding for Health Canada approved drugs and devices is decided by Provincial Health Ministries. Ontario Health (Cancer Care Ontario) (OH-CCO) is the agency of the Ministry of Health (MOH) in Ontario responsible for making recommendations to the MOH around the organization and funding of cancer services within Ontario (population of 15 million), and the PET Steering Committee of OH-CCO is responsible for providing recommendations on the introduction of new PET radiopharmaceuticals and indications. For Health Canada approved PET radiopharmaceuticals like 18F-FDG, OH-CCO (on behalf of the MOH) provides coverage based on levels of evidence and specific PET Registries are established to aid in real-world evidence collection to inform OH-CCO regarding emerging PET applications. In the case of PSMA PET/CT, adapting this model to an IND PSMA PET/CT agent, 18F-DCFPyL, necessitated the creation of a hybrid Registry-Study model to leverage the existing OH-CCO Registry structure while respecting the need for a Health Canada Clinical Trials Application (CTA) for the deployment of this agent in the province. Within the first 2 years of the registry, over 1700 men have been imaged resulting in a change in management (compared to pre-PET management plans) in over half of the men imaged. In this article, we describe the organization and deployment of the PSMA PET/CT (PREP) Registry throughout the province to provide access for men with suspected prostate cancer recurrence along with key stakeholder perspectives and preliminary results.
Systematic Review of Intrapartum Fetal Heart Rate Spectral Analysis and an Application in the Detection of Fetal Acidemia
Authors: Castro Luísa , Loureiro Maria , Henriques Teresa S. , Nunes Inês
Published: August 2021

It is fundamental to diagnose fetal acidemia as early as possible, allowing adequate obstetrical interventions to prevent brain damage or perinatal death. The visual analysis of cardiotocography traces has been complemented by computerized methods in order to overcome some of its limitations in the screening of fetal hypoxia/acidemia. Spectral analysis has been proposed by several studies exploring fetal heart rate recordings while referring to a great variety of frequency bands for integrating the power spectrum. In this paper, the main goal was to systematically review the spectral bands reported in intrapartum fetal heart rate studies and to evaluate their performance in detecting fetal acidemia/hypoxia. A total of 176 articles were reviewed, from MEDLINE, and 26 were included for the extraction of frequency bands and other relevant methodological information. An open-access fetal heart rate database was used, with recordings of the last half an hour of labor of 246 fetuses. Four different umbilical artery pH cutoffs were considered for fetuses' classification into acidemic or non-acidemic: 7.05, 7.10, 7.15, and 7.20. The area under the receiver operating characteristic curve (AUROC) was used to quantify the frequency bands' ability to distinguish acidemic fetuses. Bands referring to low frequencies, mainly associated with neural sympathetic activity, were the best at detecting acidemic fetuses, with the more severe definition (pH ≤ 7.05) attaining the highest values for the AUROC. This study shows that the power spectrum analysis of the fetal heart rate is a simple and powerful tool that may become an adjunctive method to CTG, helping healthcare professionals to accurately identify fetuses at risk of intrapartum hypoxia and to implement timely obstetrical interventions to reduce the incidence of related adverse perinatal outcomes.
Synaptic Components, Function and Modulation Characterized by GCaMP6f Ca2+ Imaging in Mouse Cholinergic Myenteric Ganglion Neurons
Authors: Margiotta Joseph F. , Smith-Edwards Kristen M. , Nestor-Kalinoski Andrea , Davis Brian M. , Albers Kathryn M. , Howard Marthe J.
Published: August 2021

The peristaltic contraction and relaxation of intestinal circular and longitudinal smooth muscles is controlled by synaptic circuit elements that impinge upon phenotypically diverse neurons in the myenteric plexus. While electrophysiological studies provide useful information concerning the properties of such synaptic circuits, they typically involve tissue disruption and do not correlate circuit activity with biochemically defined neuronal phenotypes. To overcome these limitations, mice were engineered to express the sensitive, fast Ca2+ indicator GCaMP6f selectively in neurons that express the acetylcholine (ACh) biosynthetic enzyme choline acetyltransfarse (ChAT) thereby allowing rapid activity-driven changes in Ca2+ fluorescence to be observed without disrupting intrinsic connections, solely in cholinergic myenteric ganglion (MG) neurons. Experiments with selective receptor agonists and antagonists reveal that most mouse colonic cholinergic (i.e., GCaMP6f+/ChAT+) MG neurons express nicotinic ACh receptors (nAChRs), particularly the ganglionic subtype containing α3 and β4 subunits, and most express ionotropic serotonin receptors (5-HT3Rs). Cholinergic MG neurons also display small, spontaneous Ca2+ transients occurring at ≈ 0.2 Hz. Experiments with inhibitors of Na+ channel dependent impulses, presynaptic Ca2+ channels and postsynaptic receptor function reveal that the Ca2+ transients arise from impulse-driven presynaptic activity and subsequent activation of postsynaptic nAChRs or 5-HT3Rs. Electrical stimulation of axonal connectives to MG evoked Ca2+ responses in the neurons that similarly depended on nAChRs or/and 5-HT3Rs. Responses to single connective shocks had peak amplitudes and rise and decay times that were indistinguishable from the spontaneous Ca2+ transients and the largest fraction had brief synaptic delays consistent with activation by monosynaptic inputs. These results indicate that the spontaneous Ca2+ transients and stimulus evoked Ca2+ responses in MG neurons originate in circuits involving fast chemical synaptic transmission mediated by nAChRs or/and 5-HT3Rs. Experiments with an α7-nAChR agonist and antagonist, and with pituitary adenylate cyclase activating polypeptide (PACAP) reveal that the same synaptic circuits display extensive capacity for presynaptic modulation. Our use of non-invasive GCaMP6f/ChAT Ca2+ imaging in colon segments with intrinsic connections preserved, reveals an abundance of direct and modulatory synaptic influences on cholinergic MG neurons.
A Physiology-Guided Classification of Active-Stress and Active-Strain Approaches for Continuum-Mechanical Modeling of Skeletal Muscle Tissue
Authors: Klotz Thomas , Bleiler Christian , Röhrle Oliver
Published: August 2021

The well-established sliding filament and cross-bridge theory explain the major biophysical mechanism responsible for a skeletal muscle's active behavior on a cellular level. However, the biomechanical function of skeletal muscles on the tissue scale, which is caused by the complex interplay of muscle fibers and extracellular connective tissue, is much less understood. Mathematical models provide one possibility to investigate physiological hypotheses. Continuum-mechanical models have hereby proven themselves to be very suitable to study the biomechanical behavior of whole muscles or entire limbs. Existing continuum-mechanical skeletal muscle models use either an active-stress or an active-strain approach to phenomenologically describe the mechanical behavior of active contractions. While any macroscopic constitutive model can be judged by it's ability to accurately replicate experimental data, the evaluation of muscle-specific material descriptions is difficult as suitable data is, unfortunately, currently not available. Thus, the discussions become more philosophical rather than following rigid methodological criteria. Within this work, we provide a extensive discussion on the underlying modeling assumptions of both the active-stress and the active-strain approach in the context of existing hypotheses of skeletal muscle physiology. We conclude that the active-stress approach resolves an idealized tissue transmitting active stresses through an independent pathway. In contrast, the active-strain approach reflects an idealized tissue employing an indirect, coupled pathway for active stress transmission. Finally the physiological hypothesis that skeletal muscles exhibit redundant pathways of intramuscular stress transmission represents the basis for considering a mixed-active-stress-active-strain constitutive framework.
Lack of Increase in Muscle Mitochondrial Protein Synthesis During the Course of Aerobic Exercise and Its Recovery in the Fasting State Irrespective of Obesity
Authors: Serrano Nathan , Tran Lee , Hoffman Nyssa , Roust Lori , De Filippis Elena A. , Carroll Chad C. , Patel Shivam H. , Kras Katon A. , Buras Matthew , Katsanos Christos S.
Published: August 2021

Acute aerobic exercise induces skeletal muscle mitochondrial gene expression, which in turn can increase muscle mitochondrial protein synthesis. In this regard, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), is a master regulator of mitochondrial biogenesis, and thus mitochondrial protein synthesis. However, PGC-1α expression is impaired in muscle of humans with obesity in response to acute aerobic exercise. Therefore, we sought to determine whether muscle mitochondrial protein synthesis is also impaired under the same conditions in humans with obesity. To this end, we measured mitochondrial and mixed-muscle protein synthesis in skeletal muscle of untrained subjects with (body fat: 34.7 ± 2.3%) and without (body fat: 25.3 ± 3.3%) obesity in a basal period and during a continuous period that included a 45 min cycling exercise (performed at an intensity corresponding to 65% of heart rate reserve) and a 3-h post-exercise recovery. Exercise increased PGC-1α mRNA expression in muscle of subjects without obesity, but not in subjects with obesity. However, muscle mitochondrial protein synthesis did not increase in either subject group. Similarly, mixed-muscle protein synthesis did not increase in either group. Concentrations of plasma amino acids decreased post-exercise in the subjects without obesity, but not in the subjects with obesity. We conclude that neither mitochondrial nor mixed-muscle protein synthesis increase in muscle of humans during the course of a session of aerobic exercise and its recovery period in the fasting state irrespective of obesity.

Trial Registration: The study has been registered within ClinicalTrials.gov (NCT01824173).
Intratubular, Intracellular, and Mitochondrial Angiotensin II/AT1 (AT1a) Receptor/NHE3 Signaling Plays a Critical Role in Angiotensin II-Induced Hypertension and Kidney Injury
Authors: Li Xiao Chun , Wang Chih-Hong , Leite Ana Paula Oliveira , Zhuo Jia Long
Published: August 2021

Hypertension is well recognized to be the most important risk factor for cardiovascular diseases, stroke, and end-stage kidney failure. A quarter of the world’s adult populations and 46% of the US adults develop hypertension and currently require antihypertensive treatments. Only 50% of hypertensive patients are responsive to current antihypertensive drugs, whereas remaining patients may continue to develop cardiovascular, stroke, and kidney diseases. The mechanisms underlying the poorly controlled hypertension remain incompletely understood. Recently, we have focused our efforts to uncover additional renal mechanisms, pathways, and therapeutic targets of poorly controlled hypertension and target organ injury using novel animal models or innovative experimental approaches. Specifically, we studied and elucidated the important roles of intratubular, intracellular, and mitochondrial angiotensin II (Ang II) system in the development of Ang II-dependent hypertension. The objectives of this invited article are to review and discuss our recent findings that (a) circulating and intratubular Ang II is taken up by the proximal tubules via the (AT1) AT1a receptor-dependent mechanism, (b) intracellular administration of Ang II in proximal tubule cells or adenovirus-mediated overexpression of an intracellular Ang II fusion protein selectively in the mitochonria of the proximal tubules induces blood pressure responses, and (c) genetic deletion of AT1 (AT1a) receptors or the Na+/H+ exchanger 3 selectively in the proximal tubules decreases basal blood pressure and attenuates Ang II-induced hypertension. These studies provide a new perspective into the important roles of the intratubular, intracellular, and mitochondrial angiotensin II/AT1 (AT1a) receptor signaling in Ang II-dependent hypertensive kidney diseases.
Integration of Social Context vs. Linguistic Reference During Situated Language Processing
Authors: Maquate Katja , Knoeferle Pia
Published: August 2021

Research findings on language comprehension suggest that many kinds of non-linguistic cues can rapidly affect language processing. Extant processing accounts of situated language comprehension model these rapid effects and are only beginning to accommodate the role of non-linguistic emotional, cues. To begin with a detailed characterization of distinct cues and their relative effects, three visual-world eye-tracking experiments assessed the relative importance of two cue types (action depictions vs. emotional facial expressions) as well as the effects of the degree of naturalness of social (facial) cues (smileys vs. natural faces). We predicted to replicate previously reported rapid effects of referentially mediated actions. In addition, we assessed distinct world-language relations. If how a cue is conveyed matters for its effect, then a verb referencing an action depiction should elicit a stronger immediate effect on visual attention and language comprehension than a speaker's emotional facial expression. The latter is mediated non-referentially via the emotional connotations of an adverb. The results replicated a pronounced facilitatory effect of action depiction (relative to no action depiction). By contrast, the facilitatory effect of a preceding speaker's emotional face was less pronounced. How the facial emotion was rendered mattered in that the emotional face effect was present with natural faces (Experiment 2) but not with smileys (Experiment 1). Experiment 3 suggests that contrast, i.e., strongly opposing emotional valence information vs. non-opposing valence information, might matter for the directionality of this effect. These results are the first step toward a more principled account of how distinct visual (social) cues modulate language processing, whereby the visual cues that are referenced by language (the depicted action), copresent (the depicted action), and more natural (the natural emotional prime face) tend to exert more pronounced effects.
The Relationship Between SNS Usage and Disordered Eating Behaviors: A Meta-Analysis
Authors: Zhang Juan , Wang Yihui , Li Qianru , Wu Chenggang
Published: August 2021

Social Networking Sites (SNSs) are common tools with which modern people share their lives and establish social relationships. However, some studies have found SNSs to be associated with eating disorders, although other have identified no connection between the two. To explore the interaction between SNSs and eating disorder behaviors, this study aimed to comprehensively synthesize previous studies using meta-analysis methods. Based on selection criteria, there were 87 effect sizes from 22 studies. After analysis using a three-level random-effects meta-analysis model, a positive correlation between the use of SNSs and irregular eating behaviors was found, r = 0.09 (95% CI: 0.06, 0.11; p < 0.001). In addition, by analyzing potential moderators, body mass index (r = −0.032; 95% CI: −0.058, −0.006; p = 0.019), survey methods, and sample sources was discovered could alter the relationship between SNSs and disordered eating behaviors. Specifically, there was a significantly larger association between SNSs results obtained by paper and pencil surveys and disordered eating behaviors (r = 0.114; 95% CI: 0.081, 0.147; p < 0.001) than that between SNSs results obtained by online surveys and disordered eating behaviors (r = −0.055; 95% CI: −0.102, −0.007; p < 0.01). University students showed a larger correlation between SNSs and disordered eating behavior than other samples (r = 0.089; 95% CI: 0.049, 0.129; p < 0.001). Overall, this meta-analysis confirms that the excessive use of SNSs is associated with an increased risks of disordered eating behaviors. It is hoped that this study can provide a reference for the management and intervention of dietary behaviors related to social networks in the future.
The Mediating Role of Place Attachment Dimensions in the Relationship Between Local Social Identity and Well-Being
Authors: Maricchiolo Fridanna , Mosca Oriana , Paolini Daniele , Fornara Ferdinando
Published: August 2021

Well-functioning communities provide a range of material and psychological resources that enhance well-being. The degree to which individuals see themselves as part of the local social group, or local social identity, i.e., the social identification with the community of the place where people are living, may play an important role in enhancing happiness and well-being, as well as relationships of people with their own living environment, i.e., place attachment. We hypothesized that local social identity influences well-beingviaspecific components of place attachment to the residential city/town, i.e., place identity, social relations, and lack of resources (which is the opposite of place dependence). We measured local social identity, individual well-being, interdependent happiness, and place attachment in a sample ofN= 375 participants. We tested our hypotheses by conducting a series of mediation analyses with local social identity as an independent variable, individual well-being and interdependent happiness as dependent variables, and place attachment subfactors, i.e., place identity, social relations, and lack of resources, as mediators. Results showed that the relation between local social identity and both individual well-being and interdependent happiness was positively mediated by place identity and social relations, while the lack of resources emerged as a negative mediator only in the relation between local social identity and individual well-being (not for interdependent happiness). Practical implications and future developments are discussed.
The Association Among Achievement Goal Orientations, Academic Performance, and Academic Well-Being Among Chinese Medical Students: A Cross-Sectional Study
Authors: Li Qing-lin , Zhao Ji-yang , Tian Jing , Sun Tao , Zhao Chen-xi , Guo Hai-chen , Zhu Li-yan , Gao Rui , Yang Li-bin , Cao De-pin , Zhang Shu-e
Published: August 2021

Learning motivation is a significant factor that ensures quality in medical education, and might affect the academic performance and well-being of medical students. This study aimed to explore the status of achievement goal orientations among medical students in China and to further identify the association among academic performance, academic well-being, and achievement goal orientations. Data were collected through a cross-sectional, anonymous survey conducted with 3,511 respondents (effective response rate = 81.7%), from four medical universities in China, and demographic factors, achievement goal orientations, academic performance, and academic well-being were assessed. The average score of achievement goal orientations of Chinese medical students suggested a difference in demographic factors, including sex, year of study, experience of leadership cadre, and family income. Both mastery and performance-avoidance goals were associated with academic performance, subjective academic stress, subjective learning adaptability, subjective sleep quality, and subjective well-being. Performance-approach goals were related to academic performance, subjective academic stress, and subjective learning adaptability. The achievement goal orientations of the medical students in this study were at a middle level. The findings emphasize the importance of mastery goals for promoting the academic performance and well-being of medical students. More care and attention toward achievement goal orientations can be beneficial for the improvement of the academic performance and well-being among medical students.
The Neuropsychological Profile of Severe and Enduring Anorexia Nervosa: A Systematic Review
Authors: Broomfield Catherine , Stedal Kristin , Touyz Stephen
Published: August 2021

Characteristics of Severe and Enduring Anorexia Nervosa (SE-AN) are being investigated to differentiate the patients experiencing SE-AN from those at earlier stages of the AN disease. The current systematic review was the first step in exploring neuropsychological functioning as a potentially identifying characteristic for long-term presentations. With a subgroup of AN patients reflecting a unique neuropsychological profile that is proportionate to the quantity of patients that go on to develop SE-AN, it was the aim of this review to assess neuropsychological functioning in the later stage of the disease. In accordance with PRISMA guidelines, a literature search was conducted using four electronic databases (PsycINFO, MEDLINE, Web of Science, and Scopus) for neuropsychological research on AN participants with a seven or more year illness duration. Datasets that met inclusion criteria were screened for SE-AN participants (N= 166) and neuropsychological data extracted together with potentially confounding variables and information required to conduct a quality assessment. In research investigating decision-making, participants with a SE-AN presentation demonstrated significantly lower functioning compared to healthy controls. There was conflicting evidence for differences in intellectual functioning and set-shifting abilities with no variability indicated in central coherence, memory, attention, reasoning, or processing speed. If findings from this preliminary analysis are confirmed through empirical research, implications include earlier identification of SE-AN patients and more effective treatment development.
Monoamino Oxidase A Gene Single-Nucleotide Polymorphisms and Methylation Status and the Risk of Violent Suicide Attempts in Affective Disorder Patients
Authors: Ludwig Birgit , Carlberg Laura , Kienesberger Klemens , Swoboda Patrick , Mitschek Marleen M. M. , Bernegger Alexandra , Koller Romina , Inaner Michelle , Senft Birgit , Meisner Lisa , Fischer-Hansal Daniela , Affenzeller Andreas , Huber Jasmin , Schoenthaler Silvia , Kapusta Nestor D. , Haslacher Helmuth , Aigner Martin , Weinhaeusel Andreas , Kasper Siegfried , Schosser Alexandra
Published: August 2021

Background: When investigating the neurobiology of suicidal behavior, Monoamino Oxidase A (MAOA) is one of the prime suspects to consider. Interestingly, MAOA dysregulation has also been associated with violent behavior in previous publications. In the present study, we aimed to establish an association between polymorphisms of the MAOA gene and methylation status of the MAOA gene Exon I, and suicide attempts with violent methods in a sample of affective disorder patients.

Methods: Eight hundred fourteen Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were collected for Sequenom MassARRAY® iPLEX Gold genotyping and Multiplexed and Sensitive DNA Methylation Testing.

Results: Female affective disorder patients with a history of violent suicide attempt were found to have a significantly increased frequency of the AA genotype in the rs5906957 single nucleotide polymorphism (p = 0.003). Furthermore, the MAOA gene exon I promoter region showed significantly decreased methylation in female violent suicide attempter(s) as opposed to female affective disorder patients who had no history of suicide attempt or no history of suicide attempt with violent method.

Limitations: The small sample size hampers to reveal small genetic effects as to be expected in psychiatric disorders.

Conclusions: This study offers promising findings about associations between the MAOA gene and violent suicide especially in women.