bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of the dorsolateral prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure in humans
Authors: Sesa-Ashton Gianni , Wong Rebecca , McCarthy Brendan , Datta Sudipta , Henderson Luke A , Dawood Tye , Macefield Vaughan G
Published: April 2022

Introduction

Muscle sympathetic nerve activity (MSNA) controls the diameter of arterioles in skeletalmuscle, contributing importantly to the beat-to-beat regulation of blood pressure (BP). Although brain imaging studies have shown that bursts of MSNA originate in the rostral ventrolateral medulla, other subcortical and cortical structures—including the dorsolateral prefrontal cortex (dlPFC)—contribute.

Hypothesis

We tested the hypothesis that MSNA and BP could be modulated by stimulating the dlPFC.

Method

dlPFC. In 22 individuals MSNA was recorded via microelectrodes inserted into the common peroneal nerve, together with continuous BP, electrocardiographic, and respiration.Stimulation of the right (n=22) or left dlPFC (n=10) was achieved using transcranial alternating current (tcACS; +2 to −2mA, 0.08 Hz,100 cycles), applied between the nasion and electrodes over the F3 or F4 EEG sites on the scalp.

Results

Sinusoidal stimulation of either dlPFC caused cyclicmodulation of MSNA, BP and heart rate, and a significant increase in BP.

Conclusion

We have shown, for the first time, that tcACS of the dlPFC in awake humans causes partial entrainment of MSNA, heart rate and BP, arguing for an important role of this higher-level cortical area in the control of cardiovascular function.
Hypogonadism in men
Authors: Ugo-Neff Gina , Rizzolo Denise
Published: April 2022

Hypogonadism is a clinical syndrome of testosterone deficiency that presents with nonspecific symptoms of sexual dysfunction, fatigue, and decreased strength or muscle mass. Men with obesity, diabetes, and other comorbidities are at higher risk for hypogonadism. Patients presenting with symptoms should be tested for low testosterone and treated with testosterone replacement. Testosterone therapy carries risks and must be closely monitored. Patients treated for hypogonadism may experience improvement of symptoms and quality of life.
Using the “Do-Si-Do Simulation Model” to Engage Learners
Authors: Berndt Jodi Lisbeth
Published: April 2022

The “Do-Si-Do Simulation Model” was developed to provide simulation experiences for students when resources are limited and provide nursing students insight into health care simulation as a potential nursing career. The aim of this study was to gain insight on student perceptions of the use of the model as an active learning strategy and determine if it should be used in future courses. Twenty-four students who participated in two scenarios as nurses in the simulation room and as patients/operators in the control room agreed that use of the strategy enhanced their learning. They recommended its use in future courses.
Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on low-grade appendiceal mucinous neoplasm: A single tertiary hospital experience
Authors: Kuan Tai-Chuan , Liang Wen-Yi , Lin Chun-Chi , Lin Hung-Hsin , Huang Sheng-Chieh , Cheng Ho-Shuan , Chang Shih-Ching , Jiang Jeng-Kai , Lan Yuan-Tzu
Published: April 2022

Background:

Low-grade appendiceal mucinous neoplasm (LAMN) is a rare disease, which prognostic factors were difficult to evaluate. Inflammation markers, like neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were used as prognosticators for various cancers. This study aimed to investigate the prognostic value of pretreatment NLR and PLR on LAMN.

Methods:

From January 2000 to September 2018, there were 57 patients diagnosed with LAMN in Taipei Veterans General Hospital. Patients diagnosed with mucinous cystadenoma, mucinous tumor with uncertain malignant potential before 2010 were also included based on previous classification. Clinical and pathological data were collected. Patients were separated into high-NLR (NLR-H) and low-NLR (NLR-L) groups according to cutoff value of 3. Similarly, they were separated into high-PLR (PLR-H), and low-PLR (PLR-L) groups with cutoff value of 300. Overall survival (OS) and recurrence-free survival (RFS) were analyzed.

Results:

Among all patients, the median follow-up time was 42 months. Age, gender, clinical manifestations, type of surgery, and T stage were similar in different NLR and PLR groups. Both NLR-H and PLR-H groups had higher rate of M1 stage of diseases (22.7% vs 9.4%, p = 0.04; 57.1% vs 8.8%, p < 0.01, respectively). PLR-H group had more presence of pseudomyxoma peritonei (PMP) (57.1% vs 15.2%, p = 0.03). In univariate analysis, factors such as age, gender, tumor perforation, and operation did not have impact on OS nor RFS. On the other hand, M1b stage is the only significantly poor prognostic factor on RFS (hazard ratio, 57.96, 95% CI, 5.16-651.23, p < 0.01).

Conclusion:

Both NLR-H and PLR-H had more M1 stage of diseases, but they were not correlated to OS nor RFS. PLR-H group had higher rate of presence PMP. Nevertheless, patients with LAMN and cellular PMP (M1b stage) had a higher rate of recurrence, and other factors showed no statistical difference in OS nor RFS.
Factors influencing surgeon decision-making by measuring waiting time for pediatric ventilation tube insertions
Authors: Wang Mao-Che , Chu Chia-Huei , Wang Ying-Piao
Published: April 2022

Background:

The surgeon and physician's decision-making may be influenced by many factors. The clinical practice guideline suggested that watchful waiting for 3 months should be the initial management for pediatric otitis media with effusion. The waiting time of ventilation tube insertion for pediatric patients is a proper measurement for physician decision-making. This study investigated factors influencing the waiting time for pediatric ventilation tube insertion and to explore factors influencing physician decision-making.

Methods:

Information associated with all patients under 18 years of age who received ventilation tube insertions from July 1, 2000 to December 31, 2009 were retrieved and analyzed from a nationwide, population-based administrative database. The waiting time before ventilation tube insertions from the time of diagnosis of otitis media with effusion was recorded. Certain factors that would influence the waiting time were identified. At the same time, how these factors influenced clinical decision-making were also identified.

Results:

The waiting time decreased as patient age increased (p < 0.001), and increased as the recent frequency of upper respiratory tract infection diagnosis increased (p < 0.001). Patients who received simultaneously bilateral ventilation tube insertions had shorter waiting time than those who had unilateral surgery (p < 0.01) and patients who had undergone ventilation tube insertions in a tertiary referral center generally had longer waiting times (p < 0.001).

Conclusion:

The waiting time of ventilation tube insertions for pediatric otitis media with effusion can be influenced by many factors. Patients with older age and undergone simultaneously bilateral ventilation tube insertion had shorter waiting time. Patients who had more upper respiratory tract infection episodes and who received ventilation tube insertions in a tertiary referral center setting were subject to longer waiting times.
Association Between Illness Perception and Adherence to Treatment in Slovak Patients With Hypertension
Authors: Sováriová Soósová Mária , Suchanová Renáta , Parová Valéria , Ulbrichtová Antónia , Kopčová Olívia , Rimárová Kvetoslava
Published: April 2022

Background

Lack of adherence to treatment in patients with arterial hypertension leads to poor blood pressure control, increased morbidity and mortality, and increased costs to health and social care. Regular assessment of treatment adherence as well as factors influencing it is important to improve patient adherence and consequently increase treatment efficacy. Personal beliefs, particularly illness representations, are significant factors that influence adherence.

Objective

The aim of this study was to assess the associations between adherence to treatment, illness perception, and selected sociodemographic and clinical characteristics in patients with arterial hypertension.

Methods

In this cross-sectional observational study, 235 patients with arterial hypertension completed the Hill-Bone Compliance to High Blood Pressure Therapy Scale and the Brief Illness Perception Questionnaire. Associations between variables were assessed by Spearman ρ and multiple linear regression analysis.

Results

Younger age, male gender, overall number of drugs used, and poorer beliefs related to the timeline, treatment control, and understanding were associated with higher levels of nonadherence. The final regression model significantly (P ≤ .05) explained 19.4% of the variance in diet adherence, 5.0% in appointment keeping, and 17.8% in medication adherence.

Conclusion

Comprehensive care aimed at regular evaluation of illness perceptions with an emphasis on increasing understanding of the disease and its treatment and reducing patient worries and negative emotions seems to be a relevant strategy for improving adherence to antihypertensive treatment in everyday clinical practice.
The Verran Professional Governance Scale
Authors: Weston Marla J. , Meek Paula , Verran Joyce A. , Brewer Barbara B. , Clavelle Joanne T. , Porter-O'Grady Tim , Wong Bob
Published: April 2022

This article describes psychometric testing and refinement of the Verran Professional Governance Scale (VPGS), which measures behaviors associated with professional governance. Phase 1 reduced the items on the scale based on floor and ceiling effects and redundancy of items. Phase 2 examined structural construct validity using exploratory (EFA) and confirmatory factor analysis (CFA). The final 22-item instrument demonstrates satisfactory internal consistencies and fit indices and significant positive correlation between the VPGS, job satisfaction, and control over nursing practice.
Death as a Complication of Urologic Surgery—2 Cases Identified at Autopsy
Authors: Morton Ernest , Ekpo Mfoniso , Prahlow Joseph A.
Published: April 2022

While routine medical procedures often impose some level of risk for the patient, death after routine urologic care is rare. In this series, we present 2 cases in which a relatively healthy patient ultimately died after complications, one from a prostate biopsy and one from a total nephrectomy. In case 1, a 58-year-old male died due to a 1500-mL to 2000-mL left retroperitoneal hemorrhage that occurred during insertion of a central line for sepsis treatment that resulted from an infection after a transrectal prostate biopsy. In case 2, a patient who underwent a total nephrectomy for renal cell carcinoma expired on postoperative day 7. Autopsy revealed a 1500-mL hemoperitoneum and an “unclasped” vascular surgical clip with the likely source of origin being the surgical resection site. Performance of an autopsy is essential to ascertain the cause and manner of death after medically related deaths because autopsy results can have implications on patient care, patient safety, and quality improvement.
Sinonasal Tumors With Neuroepithelial Differentiation (Olfactory Carcinoma)
Authors: Rooper Lisa M. , Bishop Justin A. , Faquin William C. , Foss Robert D. , Gallia Gary L. , Jo Vickie Y. , Lewis James S. , Nishino Michiya , Stelow Edward B. , Thompson Lester D.R. , Wenig Bruce M. , Westra William H.
Published: April 2022

Olfactory carcinoma is one of many names applied to sinonasal malignancies with histologic similarity to olfactory neuroblastoma (ONB) but cytokeratin expression or gland formation. It is unclear whether these neuroepithelial tumors represent a unified category and if they are separate from ONB and currently-recognized sinonasal carcinomas. This study aims to explore their clinicopathologic characteristics based on a large collective experience. A total of 53 sinonasal tumors with neuroepithelial differentiation were identified affecting 41 men and 12 women, median age 47 years (range: 12 to 82 y). The vast majority arose in the superior nasal cavity and presented at the high Kadish-Morita stage. Frequent histologic findings included (1) lobulated and solid growth, (2) rosettes and/or neurofibrillary stroma, (3) high-grade cytology, (4) complex, often ciliated glands, (5) nonfocal pancytokeratin expression, (6) neuroendocrine pos+itivity, and (7) variable S100-positive sustentacular cells. Twelve patients with available follow-up (48%) developed progressive disease at a median 8 months (range: 0 to 114 mo to progression), and 7 (28%) died of disease. Despite disparate historical terminology, neuroepithelial differentiation is a recurrent and recognizable histologic pattern that is associated with aggressive behavior in sinonasal tumors. While tumors with this phenotype may originate from olfactory mucosa, well-developed epithelial features warrant separation from conventional ONB and neural elements distinguish them from most sinonasal carcinomas. Although their full histogenesis remains uncertain and some heterogeneity may exist, we propose that this pattern is sufficiently distinctive to merit separate recognition as olfactory carcinoma. Use of consistent nomenclature may facilitate greater recognition of tumors with this phenotype and understanding of their pathogenesis and classification.
Associations of Chronic Burden, Sleep Characteristics, and Metabolic Syndrome in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Johnson Dayna A. , Knutson Kristen , Colangelo Laura A. , Hale Lauren , Redline Susan , Carnethon Mercedes , Kershaw Kiarri N.
Published: April 2022

Objective

Chronic exposure to stress is associated with metabolic syndrome (MetS), but the mechanism is unclear. We investigated associations between chronic burden, sleep and MetS in the CARDIA Study.

Methods

Chronic burden was self-reported (2000-2001) according to experiences with stressors for longer than 6 months. Wrist actigraphy-measured sleep duration and sleep efficiency were collected for 6-days; sleep duration, sleep quality and daytime sleepiness were self-reported (2003-2004). MetS was measured during the clinic visit, 2005-2006. Multivariable logistic and Cox proportional hazard models were fit to determine the associations of interest. Mediation by sleep was assessed using the product of coefficients approach.

Results

Among participants (N = 606), the average age was 40 years (standard deviation = 3.6), 58% were female, and 43% were Black. The prevalence of chronic burden, short sleep (<6 hours), and MetS was 35%, 43% and 20.5%, respectively. High vs. low chronic burden was associated with shorter self-reported sleep duration and higher daytime sleepiness. Chronic burden was associated with 1.85 higher odds (95% confidence interval:1.11, 3.09) of MetS. Sleep characteristics were not associated with MetS. There was no evidence that sleep mediated the chronic burden-MetS relation.

Conclusion

Burden of chronic stress may be an emerging novel risk factor for both poor sleep and MetS.
Cytomegalovirus and Toxoplasma Gondii Serostatus Prospectively Correlated With Problems in Self-Regulation but not Executive Function Among Older Adults
Authors: Segerstrom Suzanne C. , Reed Rebecca G. , Karr Justin E.
Published: April 2022

Objective

Cytomegalovirus (CMV) and Toxoplasma gondii are organisms that may infect the brain and have cognitive and behavioral consequences. We hypothesized that these latent infections would be prospectively associated with poorer cognition and more problems in self-regulation among older adults.

Methods

Older adults (n = 138, mean age = 75.5 years, 59% women) had CMV and T. gondii serostatus tested, crystallized intelligence estimated (North American Adult Reading Test), and executive function (EF; e.g., Trail Making Test) and self-regulation (Behavior Regulation Inventory of Executive Function—Adult) assessed in visits occurring every 6 months (mean visits = 16).

Results

CMV+ people (79%) had significantly poorer self-regulation versus CMV− people (21%; behavioral regulation: γ = 0.108, 95% confidence interval [CI] = 0.009–0.206; metacognition: γ = 0.117, 95% CI = 0.005–0.229), but not intelligence or EF. T. gondii+ people (24%) were not significantly different from T. gondii− people (76%) on any outcome. However, T. gondii+ men had better self-regulation versus T. gondii− men, and the opposite was true of women (behavioral regulation interaction: γ = 0.267, 95% CI = 0.093–0.441).

Conclusions

CMV latent infection was associated with more problems in self-regulation, and the magnitude of this difference was clinically significant. T. gondii latent infection was associated with more problems, but only for women. Latent infection might associate with self-regulation but not EF because of factors influencing self-regulation but not neuropsychological test performance, such as values and emotion. Efforts to link latent infection with EFs might, in the future, include the application of those functions to self-regulation in daily life.
Determining educational assessment criteria for patellar-tendon-bearing impressions for transtibial prosthetic sockets: A Delphi study
Authors: Falbo Kierra J. , Morgan Sara J. , Brinkmann John T.
Published: April 2022

Background:

Validated criteria to guide assessment of student performance in clinical tasks in prosthetics and orthotics education have not been established. Lack of established criteria and assessment methods presents challenges in evaluating student performance on clinical tasks, such as taking impressions for patellar-tendon-bearing (PTB) sockets.

Objectives:

To establish assessment criteria for the PTB impression process for use in educational settings.

Study design:

Delphi consensus process.

Methods:

Initial Delphi survey items were based on interviews with prosthetic instructors and focus groups with prosthetic students. Expert prosthetic educators were then identified by purposive sampling to complete multiple-round Internet-based Delphi surveys. The Delphi surveys asked experts to indicate their level of agreement on various assessment methods and criteria in PTB education. Consensus for survey items was reviewed after each survey round and used to determine the content of and need for subsequent rounds.

Results:

Fourteen experts completed two Delphi survey rounds. Items were categorized into educational materials/strategies, impression stages/materials, measurement tools, measurements taken, assessment during impression, assessment after impression, feedback, student self-assessment, and grading. In two survey rounds, 40 items guiding assessment methods and criteria for PTB impressions achieved 80% consensus.

Conclusions:

A high level of consensus was achieved in two survey rounds. Lower levels of consensus were reached on specific objective criteria, such as use of measurement thresholds when evaluating student impressions. Standardized assessment of student performance on PTB impression-taking instead relies primarily on qualitative assessments based on instructor expertise.
Ambient Temperature and Dengue Hospitalisation in Brazil: A 10-year period two-stage case-design time series analysis
Authors: Lopes Rafael , Basagaña Xavier , Bastos Leonardo S. L. , Bozza Fernando A. , Ranzani Otavio T.
Published: April 2022

Climate factors are known to influence seasonal patterns of dengue transmission. However, little is known about the effect of extremes of temperature on the severity of dengue infection, such as hospital admission. We aimed to quantify the effect of ambient temperature on dengue hospitalisation risk in Brazil. We retrieved daily dengue hospitalisation counts by each of 5,565 municipalities across the 27 states of Brazil from 1st of January 2010 to 31st of December 2019, from the Brazilian Public Hospital Admission System (“SIH”). We obtained average daily ambient temperature for each municipality from the ERA5-land product reanalysis. We combined distributed lag non-linear models with time stratified design model framework to pool a relative risk (RR) estimate for dose-response and lag-response structures for the association of temperature and Dengue hospitalisation. We estimate the overall dengue hospitalisation RR for the whole country as well for each of the five macro-regions by meta-analysing state level estimates. 579,703 hospital admissions due to dengue occurred over the 10 years’ period of 2010 to 2019. We observed a positive association between high temperatures and high risk of hospitalisation for Brazil. The overall RR for dengue hospitalisation was 2.185 (95% CI 1.457-3.276) at the 50th percentile of temperature and 2.385 (95% CI 1.556-3.655) at 95th percentile of temperature for Brazil. We also found lag effects of heat on hospitalisation, particularly an immediate augmented risk to hospitalisation, both at the 50th percentile and 95th. High temperatures are associated with an increase in the risk of hospitalisation by dengue. These findings may guide preparedness and mitigation policies during dengue season outbreaks, particularly on the health-care demand.
α1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF
Authors: Ishikawa Genta , Peng Xueyan , McGovern John , Woo Sam , Perry Carrighan , Liu Angela , Yu Sheeline , Ghincea Alexander , Sun Huanxing , Ryu Changwan , Herzog Erica L.
Published: April 2022

Idiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lung’s adrenergic nerve supply drives the accumulation of αSMA-expressing fibroblasts via a mechanism involving α1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a αSMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGFβ1-stimulated normal human lung fibroblasts treated with TGFβ1 and Noradrenaline expressed ADRA1D and developed reduced αSMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed α1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and α1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.
Localization of Abnormal Brain Regions in Parkinsonian Disorders: An ALE Meta-Analysis
Authors: Ellis Elizabeth G. , Joutsa Juho , Morrison-Ham Jordan , Caeyenberghs Karen , Corp Daniel T.
Published: April 2022

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration syndrome (CBS) and multiple system atrophy (MSA). Neuroimaging studies have yielded insights into parkinsonism; however it remains unclear whether there is a common neural substrate amongst disorders. The aim of the present meta-analysis was to identify consistent brain alterations in parkinsonian disorders (PD, PSP, CBS, MSA) both individually, and combined, to elucidate the shared substrate of parkinsonism. 33,505 studies were systematically screened following searches of MEDLINE Complete and Embase databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 126 neuroimaging studies (64 PD; 25 PSP; 18 CBS; 19 MSA) utilizing anatomical MRI, perfusion or metabolism positron emission tomography and single photon emission computed tomography. Abnormality of the caudate, thalamus, middle frontal and temporal gyri was common to all parkinsonian disorders. Localizations of commonly affected brain regions in individual disorders aligned with current diagnostic imaging markers, localizing the midbrain in PSP, putamen in MSA-parkinsonian variant and brainstem in MSA-cerebellar variant. Regions of the basal ganglia and precuneus were most commonly affected in PD, while CBS was characterized by caudate abnormality. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders. Findings support the notion that parkinsonism may share a common neural substrate, independent of the underlying disease process, while also highlighting characteristic patterns of brain abnormality in each disorder.
Evolution and co-evolution of the suck behaviour, a postcopulatory female resistance trait that manipulates received ejaculate
Authors: Singh Pragya , Brand Jeremias N. , Schärer Lukas
Published: April 2022

Sexual conflicts over the post-mating fate of received ejaculate can favour traits in one sex that are costly to the other. Reciprocally mating hermaphrodites face unique challenges as they mate simultaneously in both the male and female role, potentially leading to receipt of unwanted ejaculate. Reciprocal mating can then give rise to postcopulatory female resistance traits that allow manipulation of received ejaculate. A putative example is the suck behaviour, observed in the flatworm genusMacrostomum. It involves the sperm recipient placing its pharynx over its own female genital opening and appearing to suck, likely removing received ejaculate after mating. The genus also contains hypodermically-inseminating species that presumably exhibit unilateral mating and have not been observed to suck. Here, we examine the evolution of the suck behaviour inMacrostomum, aiming to document the mating behaviour in 64 species. First, we provide videographic evidence that ejaculate is indeed removed during the suck behaviour in a reciprocally mating species,Macrostomum hamatum. Next, we show evolutionary positive correlations between the presence, duration and frequency of reciprocal mating behaviour and the suck behaviour, providing clear evidence that the suck behaviour co-evolves with reciprocal mating behaviour. Finally, we show an association between reproductive behaviour and reproductive morphology, suggesting that reproductive morphology can be used for inferring the behavioural mating strategy of a species. Together our study demonstrates sexual antagonistic coevolution leading to the evolution of a postcopulatory behavioural trait that functions as a female counter-adaptation allowing individuals to gain control over received ejaculate in a hermaphroditic sexual system.
Spinosaurids as ‘subaqueous foragers’ undermined by selective sampling and problematic statistical inference
Authors: Myhrvold Nathan , Sereno Paul C. , Baumgart Stephanie L. , Formoso Kiersten K. , Vidal Daniel , Fish Frank E. , Henderson Donald M.
Published: April 2022

Fabbri et al.1 claim that the huge sail-backed dinosaur Spinosaurus aegyptiacus and the spinosaurid Baryonyx were “subaqueous foragers,” diving underwater in pursuit of prey, based on their measure of bone “compactness.” Using thin-sections and computed tomographic (CT) scans of thigh bone (femur) and trunk rib from various living and extinct vertebrates, they claim to be able to distinguish taxa with “aquatic habits” from others. Their conclusions are undermined by selective bone sampling, inaccuracies concerning spinosaurid bone structure, faulty statistical inferences, and novel redefinition of the term “aquatic.”
Onlinemeta: A Web Server for Meta-Analysis Based on Shiny Framework
Authors: Dai Weiyuntian , Yi Yonglin , Lin Anqi , Zhou Chaozheng , Zhang Jian , Wang Shixiang , Sun Min , Luo Peng
Published: April 2022

Meta-analysis is a common statistical method used to summarize multiple studies that cover the same topic. It can provide less biased results and explain heterogeneity between studies. Although there exists a variety of meta-analysis softwares, they are rarely both convenient to use and capable of comprehensive analytical functions. As a result, we are motivated to establish a meta-analysis web tool called Meta-Analysis Online (Onlinemeta). Onlinemeta includes three major modules: risk bias analysis, meta-analysis and network meta-analysis. The risk bias analysis module can produce heatmaps and histograms, whereas the meta-analysis module accepts many types of data as input, including dichotomous variables, single-armed dichotomous variables, continuous variables, single-armed continuous variables, survival data, deft method and diagnostic experiments, and outputs well-tuned forest plots, sensitivity analysis forest plots, funnel plots, comparison table of effects, SROC curve, and crosshair plots. For network meta-analysis module, the tool can process dichotomous variables or continuous variables, and generate network plots, forest plots, SUCRA (Surface Under the Cumulative Ranking) plots, rank plots and heatmaps. Onlinemeta is available athttps://smuonco.Shinyapps.io/Onlinemeta/.
Catecholaminergic cell type-specific expression of Cre recombinase in knock-in transgenic rats generated by the Combi-CRISPR technology
Authors: Matsushita Natsuki , Nishizawa Kayo , Kato Shigeki , Iguchi Yoshio , Fukabori Ryoji , Takeuchi Kosei , Miyasaka Yoshiki , Mashimo Tomoji , Kobayashi Kazuto
Published: April 2022

Background

Cell groups containing catecholamines provide a useful model to study the molecular and cellular mechanisms underlying the morphogenesis, physiology, and pathology of the central nervous system. For this purpose, it is necessary to establish a system to induce catecholaminergic group-specific expression of Cre recombinase. Recently, we introduced a gene cassette encoding 2A peptide fused to Cre recombinase into the site between the C-terminus and translational termination codons of the rat tyrosine hydroxylase (TH) open reading frame by the Combi-CRISPR technology, which is a genomic editing method to enable an efficient knock-in (KI) of long DNA sequence into a target site. However, the expression patterns of the transgene and its function as well as the effect of the mutation on the biochemical and behavioral phenotypes in the KI strains have not been characterized yet.

New Method

We aimed to evaluate the usefulness of TH-Cre KI rats as an experimental model for investigating the structure and function of catecholaminergic neurons in the brain.

Results

We detected cell type-specific expression of Cre recombinase and site-specific recombination activity in the representative catecholaminergic groups in the TH-Cre KI rat strains. In addition, we measured TH expression level and catecholamine accumulation in the brain regions, and spontaneous locomotion, indicating that catecholamine metabolism and general behavior are apparently normal in these KI rats.

Conclusions

TH-Cre KI rat strains produced by the Combi-CRISPR system offer a beneficial model to study the molecular and cellular mechanics for the morphogenesis, physiology, and pathology of catecholamine-containing neurons in the brain.
Extensive diversity and rapid turnover of phage defense repertoires in cheese-associated bacterial communities
Authors: Somerville Vincent , Schowing Thibault , Chabas Hélène , Schmidt Remo S. , von Ah Ueli , Bruggmann Rémy , Engel Philipp
Published: April 2022

Phages are key drivers of genomic diversity in bacterial populations as they impose strong selective pressure on the evolution of bacterial defense mechanisms across closely related strains. The pan-immunity model suggests that such diversity is maintained because the effective immune system of a bacterial species is the one distributed across all strains present in the community. However, only few studies have analyzed the distribution of bacterial defense systems at the community-level, mostly focusing on CRISPR and comparing samples from complex environments. Here, we studied 2’778 bacterial genomes and 158 metagenomes from cheese-associated communities, which are dominated by a few bacterial taxa and occur in relatively stable environments. We find that nearly identical strains of cheese-associated bacteria contain diverse and highly variable arsenals of innate and adaptive (i.e CRISPR-Cas) immunity suggesting rapid turnover of defense mechanisms in these communities. CRISPR spacer abundance correlated with the abundance of matching target sequences across the metagenomes providing evidence that the identified defense repertoires are functional and under selection. While these characteristics align with the pan-immunity model, the detected CRISPR spacers only covered a subset of the phages previously identified in cheese, suggesting that CRISPR does not provide complete immunity against all phages, and that the innate immune mechanisms may have complementary roles. Our findings show that the evolution of bacterial defense mechanisms is a highly dynamic process and highlight that experimentally tractable, low complexity communities such as those found in cheese, can help to understand ecological and molecular processes underlying phage-defense system relationships.

Importance

Bacteria are constantly exposed to phage predation and hence harbor highly diverse defense arsenals. According to the pan-immunity hypothesis the effective immune system of a bacterial species is not the one encoded in a single genome but in the entire community. However, few studies have investigated how defense systems are distributed within communities. Here, we carried out (meta)genomic analyses of bacterial communities used in cheesemaking. These are tractable communities of biotechnological interest which house few bacterial species and are exposed to high phage pressure. In line with the pan-immunity hypothesis, we find that nearly identical strains of cheese-associated bacteria contain highly variable arsenals of innate and adaptive immunity. We provide evidence for the functional importance of this diversity, and reveal that CRISPR alone does not provide complete immunity against all phages. Our findings can have implications for the design of robust synthetic communities used in biotechnology and the food industry.
Prenatal development of neonatal vocalizations
Authors: Narayanan Darshana Z. , Takahashi Daniel Y. , Kelly Lauren M. , Hlavaty Sabina I. , Huang Junzhou , Ghazanfar Asif A.
Published: April 2022

Human and non-human primates produce rhythmical sounds as soon as they are born. These early vocalizations are important for soliciting the attention of caregivers. How they develop, remains a mystery. The orofacial movements necessary for producing these vocalizations have distinct spatiotemporal signatures. Therefore, their development could potentially be tracked over the course of prenatal life. We densely and longitudinally sampled fetal head and orofacial movements in marmoset monkeys using ultrasound imaging. We show that orofacial movements necessary for producing rhythmical vocalizations differentiate from a larger movement pattern that includes the entire head. We also show that signature features of marmoset infant contact calls emerge prenatally as a distinct pattern of orofacial movements. Our results establish that aspects of the sensorimotor development necessary for vocalizing occur prenatally, even before the production of sound.
A novel PNGase Rc for improved protein N-deglycosylation in bioanalytics and HDX-MS epitope mapping under challenging conditions
Authors: Gramlich Marius , Maier Sandra , Kaiser Philipp D. , Traenkle Bjoern , Wagner Teresa R. , Voglmeir Josef , Stoll Dieter , Rothbauer Ulrich , Zeck Anne
Published: April 2022

N-linked glycosylation is a ubiquitous posttranslational modification of proteins. While it plays an important role in the biological function of proteins, it often poses a major challenge for their analytical characterization. Currently available peptide N-glycanases (PNGases) are often inefficient at deglycosylating proteins due to sterically inaccessible N-glycosylation sites. This usually leads to poor sequence coverage in bottom-up analysis using liquid chromatography with tandem mass spectrometry (LC-MS) and makes it impossible to obtain an intact mass signal in top-down MS analysis. In addition, most PNGases operate optimally only in the neutral to slightly acidic pH range and are severely compromised in the presence of reducing and denaturing substances, which limits their use for advanced bioanalysis based on hydrogen-deuterium exchange in combination with mass spectrometry (HDX-MS).

Here, we present a novel peptide N-glycanase from Rudaea cellulosilytica (PNGase Rc) for which we demonstrate broad substrate specificity for N-glycan hydrolysis from multiply occupied and natively folded proteins. Our results show that PNGase Rc is functional even under challenging, HDX quench conditions (pH 2.5, 0 °C) and in the presence of 0.4 M Tris(2-carboxyethyl)phosphine (TCEP), 4 M urea and 1 M guanidinium chloride (GdmCl). Most importantly, we successfully applied the PNGase Rc in an HDX-MS workflow to determine the epitope of a nanobody targeting the extracellular domain of human signal-regulating protein alpha (SIRPα).
Molecular basis of indispensable accuracy of mammalian miRNA biogenesis
Authors: Zapletal David , Taborska Eliska , Pasulka Josef , Malik Radek , Kubicek Karel , Zanova Martina , Much Christian , Sebesta Marek , Buccheri Valeria , Horvat Filip , Jenickova Irena , Prochazkova Michaela , Prochazka Jan , Pinkas Matyas , Novacek Jiri , Joseph Diego F. , Sedlacek Radislav , O’Carroll Dónal , Stefl Richard , Svoboda Petr
Published: April 2022

Mammalian Dicer is the gatekeeper into the essential gene-regulating miRNA pathway. What is committing mammalian Dicer to the miRNA pathway remains unknown. We report that Dicer’s highly conserved DExD/H helicase domain is the key structural element supporting accurate miRNA biogenesis. While ATPase activity of the domain is non-essential, its loss is lethal in mice. It is required during canonical miRNA biogenesis for efficient recognition, high-fidelity cleavage, and strand selection. Structure of Dicer-miRNA precursor complexes showed that the DExD/H domain acquired helicase-unrelated function defining Dicer conformations, which affect substrate loading and facilitate pre-selection of miRNA precursors. Dicer lacking the DExD/H domain favors conformations enabling reduced substrate selectivity and supporting RNA interference, a different small RNA pathway. Therefore, Dicer’s DExD/H domain ensures indispensable high-fidelity precursor processing of mammalian miRNAs, which constitutes a structural “mold” for adaptive miRNA evolution.
Melanocortin receptor agonist melanotan-II microinjected in the nucleus accumbens decreases appetitive and consumptive responding for food
Authors: Eliason Nicole , Martin Lynne , Low Malcolm J. , Sharpe Amanda L.
Published: April 2022

Rationale. Obesity is a major health problem worldwide. An understanding of the factors that drive feeding behaviors is key to the development of pharmaceuticals to decrease appetite and consumption. Proopiomelanocortin (POMC), the melanocortin peptide precursor, is essential in the regulation of body weight and ingestive behaviors. Deletion of POMC or impairment of melanocortin signaling in the brain results in hyperphagic obesity. Neurons in the hypothalamic arcuate nucleus produce POMC and project to many areas including the nucleus accumbens (NAcc), which is well established in the rewarding and reinforcing effects of both food and drugs of abuse.

Objective

These studies sought to determine the role of melanocortins in the NAcc on consumption of and motivation to obtain access to standard rodent chow.

Methods

Male, C57BL/6J mice were microinjected bilaterally into the NAcc (100 nl/side) with the melanocortin receptor 3/4 agonist melanotan-II (MT-II; 0.1, 0.3, and 1 nmol), and ingestive behaviors were examined in both home cage and operant food self-administration experiments. In addition, the ability of MT-II in the NAcc to produce aversive properties or affect metabolic rate were tested.

Results

MT-II injected into the NAcc significantly decreased consumption in both home cage and operant paradigms, and furthermore decreased appetitive responding to gain access to food. There was no development of conditioned taste avoidance or change in metabolic parameters following anorexic doses of MT-II. Conclusions. MT-II in the NAcc decreased both the motivation to eat and the amount of food consumed without inducing an aversive state or affecting metabolic rate, suggesting a role for melanocortin signaling in the ventral striatum that is selective for appetite and satiety without affecting metabolism or producing an aversive state.
A complete allosteric map of a GTPase switch in its native network
Authors: Mathy Christopher J.P. , Mishra Parul , Flynn Julia M. , Perica Tina , Mavor David , Bolon Daniel N.A. , Kortemme Tanja
Published: April 2022

Allosteric regulation is central to protein function in cellular networks1. However, despite technological advances2,3 most studies of allosteric effects on function are conducted in heterologous environments2,4,5, limiting the discovery of allosteric mechanisms that rely on endogenous binding partners or posttranslational modifications to modulate activity. Here we report an approach that enables probing of new sites of allosteric regulation at residue-level resolution in essential eukaryotic proteins in their native biological context by comprehensive mutational scanning. We apply our approach to the central GTPase Gsp1/Ran. GTPases are highly regulated molecular switches that control signaling, with switching occurring via catalyzed GTP hydrolysis and nucleotide exchange. We find that 28% of 4,315 assayed mutations in Gsp1/Ran are highly deleterious, showing a toxic response identified by our assay as gain-of-function (GOF). Remarkably, a third of all positions enriched for GOF mutations (20/60) are outside the GTPase active site. Kinetic analysis shows that these distal sites are allosterically coupled to the active site, including a novel cluster of sites that alter the nucleotide preference of Gsp1 from GDP to GTP. We describe multiple distinct mechanisms by which allosteric mutations alter Gsp1/Ran cellular function by modulating GTPase switching. Our systematic discovery of new regulatory sites provides a functional map relevant to other GTPases such as Ras that could be exploited for targeting and reprogramming critical biological processes.
Lossless end-to-end transport of small molecules through micron-length DNA nanochannels
Authors: Li Yi , Maffeo Christopher , Joshi Himanshu , Aksimentiev Aleksei , Ménard Brice , Schulman Rebecca
Published: April 2022

Designed and engineered protein and DNA nanopores can sense and characterize single molecules and control transmembrane transport of molecular species. However, designed biomolecular pores are less than 100 nm in length and are used primarily for transport across lipid membranes. Nanochannels that span longer distances could be used as conduits for molecules between non-adjacent compartments or cells. Here, we design microns-long, 7 nm diameter DNA nanochannels that small molecules can traverse according to the laws of continuum diffusion. Binding DNA origami caps to channel ends eliminates transport and demonstrates that molecules diffuse from one channel end to the other rather than permeating through channel walls. These micron-length nanochannels can also grow, form interconnects, and interface with living cells. This work thus shows how to construct multifunctional, dynamic agents that control molecular transport, opening new ways of studying intercellular signaling and modulating molecular transport between synthetic and living cells.

Abstract Figure
Structural basis of mammalian Complex IV inhibition by steroids
Authors: Di Trani Justin , Moe Agnes , Riepl Daniel , Saura Patricia , Kaila Ville R. I. , Brzezinski Peter , Rubinstein John L.
Published: April 2022

The mitochondrial electron transport chain maintains the proton motive force that powers ATP synthesis. The energy for this process comes from oxidation of NADH and succinate, with the electrons from this oxidation passed via intermediate carriers to oxygen. Complex IV (CIV), the terminal oxidase, transfers electrons from the intermediate electron carrier cytochrome c to oxygen, contributing to the proton motive force in the process. Within CIV, protons move through the K- and D-pathways during turnover. The former is responsible for transferring two protons to the enzyme’s catalytic site upon reduction of the site, where they eventually combine with oxygen and electrons to form water. CIV is the main site for respiratory regulation, and although previous studies showed that steroid-binding can regulate CIV activity little is known about how this regulation occurs. Here we characterize the interaction between CIV and steroids using a combination of kinetic experiments, structure determination, and molecular simulations. We show that molecules with a sterol moiety, such as glyco-diosgenin and cholesteryl hemisuccinate, reversibly inhibit CIV. Flash photolysis experiments probing the high-speed equilibration of electrons within CIV demonstrate that binding of these molecules inhibits proton uptake through the K-pathway. Single particle cryo-EM of CIV with glyco-diosgenin reveals a previously undescribed steroid-binding site adjacent to the K-pathway, and molecular simulations suggest that the steroid binding modulates the conformational dynamics of key residues and proton transfer kinetics within this pathway. The binding pose of the sterol group sheds light on possible structural gating mechanisms in the CIV catalytic cycle.

SIGNIFICANCE STATEMENT

Mammalian complex IV (CIV), the final complex of the mitochondrial electron transport chain, uses electrons from cytochrome c to reduce oxygen to water, driving aerobic life. Although CIV functions as the main site for respiratory regulation, there is little structural or biochemical information on how this regulation occurs. Previous studies provided evidence of CIV regulation by steroids, but the steroid binding site and regulatory mechanism remain unclear. Using single particle cryogenic electron microscopy, we discover the binding site of the steroid-derived detergent, glyco-diosgenin. Results from flash photolysis kinetic experiments with CIV in the presence of glyco-diosgenin and cholesterol hemisuccinate are combined with cryo-EM and molecular simulations to elucidate how steroid binding limits proton uptake by the complex.
Automated decision-making
Authors: Ivanov Stanislav Hristov
Published: April 2022

Purpose

This paper aims to analyse three decision-making approaches that involve humans and artificial autonomous agents, namely, human “in the loop”, “on the loop” and “out of the loop” and identifies the decision characteristics that determine the choice of a decision-making approach.

Design/methodology/approach

This is a conceptual paper that analyses the relationships between the human and the artificial autonomous agents in the decision-making process from the perspectives of the agency theory, sustainability, legislation, economics and operations management.

Findings

The paper concludes that the human “out of the loop” approach is most suitable for quick, standardised, frequent decisions with low negative consequences of a wrong decision by the artificial intelligence taken within a well-defined context. Complex decisions with high outcome uncertainty that involve significant ethical issues require human participation in the form of a human “in the loop” or “on the loop” approach. Decisions that require high transparency need to be left to humans.

Originality/value

The paper evaluates the decision-making approaches from the perspectives of the agency theory, sustainability, legislation, economics and operations management and identifies the decision characteristics that determine the choice of a decision-making approach.