bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-passive Verbal Periphrases in the Romance Languages
Authors: Laca Brenda
Published: October 2021

Verbal periphrases combine two verbal forms that share their arguments. One of the forms, [V2], lexically determines most of the argument structure of the whole construction, whereas the other, [V1], contributes the sort of abstract meaning usually associated with functional categories in the realms of tense, aspect, and modality and is often classified as a (semi-)auxiliary. In most cases, [V2] appears in a fixed nonfinite form (infinitive, gerund, or participle), whereas the inflection on [V1] is variable; the periphrastic pattern may also include a preposition introducing the nonfinite form.

Research on verbal periphrases has concentrated on the differences between periphrastic patterns and free patterns of complementation or adjunction involving nonfinite clauses, on the syntactic analysis of those patterns, and on their semantic classification. The renewed interest in the field in recent years has two sources. On the one hand, research on grammaticalization has emphasized the importance of periphrases for our understanding of the way in which exponents for grammatical meanings emerge diachronically from lexical constructions. On the other hand, work in generative syntax (in the so-called cartographic approach) has taken periphrases as evidence for the postulated existence of highly articulated functional layers above a core verb phrase headed by a lexical verb. The bulk of nonpassive verbal periphrases either modify Aktionsart or express viewpoint aspect or relative tense. Research has revealed considerable differences in their inventory and in the status of cognate periphrases across Romance, as well as some parallel or convergent developments.
Antibacterial polysaccharide-based hydrogel dressing containing plant essential oil for burn wound healing
Authors: Wang Huanhuan , Liu Yang , Cai Kun , Zhang Bin , Tang Shijie , Zhang Wancong , Liu Wenhua
Published: October 2021

Background

Polysaccharide-based hydrogels have been developed for many years to treat burn wounds. Essential oils extracted from aromatic plants generally exhibit superior biological activity, especially antibacterial properties. Studies have shown that antibacterial hydrogels mixed with essential oils have great potential for burn wound healing. This study aimed to develop an antibacterial polysaccharide-based hydrogel with essential oil for burn skin repair.

Methods

Eucalyptus essential oil (EEO), ginger essential oil (GEO) and cumin essential oil (CEO) were employed for the preparation of effective antibacterial hydrogels physically crosslinked by carboxymethyl chitosan (CMC) and carbomer 940 (CBM). Composite hydrogels were prepared and characterized using antimicrobial activity studies, Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, gas chromatography-mass spectrometery, rheological analysis, viscosity, swelling, water loss rate and water vapor transmission rate studies. In addition, the biocompatibility of hydrogels was evaluated in vivo by cytotoxicity and cell migration assays and the burn healing ability of hydrogels was tested in vivo using burn-induced wounds in mice.

Results

The different essential oils exhibited different mixing abilities with the hydrogel matrix (CMC and CBM), which caused varying levels of reduction in essential oil hydrogel viscosity, swelling and water vapor transmission. Among the developed hydrogels, the CBM/CMC/EEO hydrogel exhibited optimal antibacterial activities of 46.26 ± 2.22% and 63.05 ± 0.99% against Staphylococcus aureus and Escherichia coli, respectively, along with cell viability (>92.37%) and migration activity. Furthermore, the CBM/CMC/EEO hydrogel accelerated wound healing in mouse burn models by promoting the recovery of dermis and epidermis as observed using a hematoxylin–eosin and Masson’s trichrome staining assay. The findings from an enzyme-linked immunosorbent assay demonstrated that the CBM/CMC/EEO hydrogel could repair wounds through interleukin-6 and tumor necrosis factor-α downregulation and transforming growth factor-β, vascular endothelial growth factor (VEGF) and epidermal growth factor upregulation.

Conclusions

This study successfully prepared a porous CBM/CMC/EEO hydrogel with high antibacterial activity, favorable swelling, optimal rheological properties, superior water retention and water vapor transmission performance and a significant effect on skin repair in vitro and in vivo. The results indicate that the CBM/CMC/EEO hydrogel has the potential for use as a promising burn dressing material for skin burn repair.
Detection of steroid and thyroid hormones in mammalian teeth
Authors: Hudson Justine M , Matthews Cory J D , Watt Cortney A
Published: October 2021

Endocrine tools can provide an avenue to better understand mammalian life histories and predict how individuals and populations may respond to environmental stressors; however, few options exist for studying long-term endocrine patterns in individual marine mammals. Here, we (i) determined whether hormones could be measured in teeth from four marine mammal species: narwhal (Monodon monoceros), beluga (Delphinapterus leucas), killer whale (Orcinus orca) and Atlantic walrus (Odobenus rosmarus rosmarus); (ii) validated commercially available enzyme immunoassay kits for use with tooth extracts; and (iii) conducted biological validations for each species to determine whether reproductive hormone concentrations in teeth correlated with age of sexual maturity. Tooth extracts from all species had measurable concentrations of progesterone, testosterone, 17β-estradiol, corticosterone, aldosterone and triiodothyronine (T3); however, cortisol was undetectable. Parallelism between the binding curves of assay kit standards and serially diluted pools of tooth extract for each species was observed for all measurable hormones. Slopes of accuracy tests ranged from 0.750 to 1.116, with r2 values ranging from 0.977 to 1.000, indicating acceptable accuracy. Biological validations were inconsistent with predictions for each species, with the exception of female killer whales (n = 2), which assumed higher progesterone and testosterone concentrations in mature individuals than immature individuals. Instead, we observed a decline in progesterone and testosterone concentrations from infancy through adulthood in narwhal (n = 1) and walruses (n = 2) and higher reproductive hormone concentrations in immature individuals than mature individuals in belugas (n = 8 and 10, respectively) and male killer whales (n = 1 and 2, respectively). While unexpected, this pattern has been observed in other taxa; however, further analytical and biological validations are necessary before this technique can be used to assess individual mammalian endocrine patterns.
Individualized surgical treatment for patients with tumours of the cervicothoracic junction
Authors: Wang Shuai , Chen Zhencong , Zhang Ke , Tan Lijie , Ge Di , Qi Fazhi , Zhang Yong , Zhu Ting , Chen Zenggan , Wang Qun , Jiang Wei
Published: October 2021

OBJECTIVES

The cervicothoracic junction is a special section that connects the neck, thoracic cavity, mediastinum and axilla. Tumours in the region often invade or compress surrounding tissues and organs, which makes the surgical treatment difficult.

METHODS

A retrospective analysis involving 69 patients with tumours at the cervicothoracic junction. Clinical data with regard to manifestation, surgical approach, resection degree, outcome and pathological types were collected.

RESULTS

A total of 48 cases of asymptomatic patients and 21 cases of patients with ≥1 clinical manifestation were enrolled in the study. Twenty-seven patients received radical resection with video-assisted thoracoscopic surgery. Anterior approach was the predominant treatment method in open surgery (25 cases, 36.2%), while the anterolateral approach was used in 8 cases (6 cases of hemiclamshell incisions and 2 cases of trap-door incisions). In addition, we observed 1 case of posterior approach, 2 cases of posterolateral approach and 1 case of supraclavicular approach combined with posterolateral approach. Pathological examination results revealed 67 cases of radical resection and 2 cases of microscopic residual. Neurilemmoma was the most widespread pathological type (30 cases, 43.5%), followed by tumour originating from fibrous tissues (5 cases, 7.2%). A 3-year overall survival rate of the 69 patients was 89.9%, while a 5-year overall survival rate was 85.5%.

CONCLUSIONS

Tumours associated with the cervicothoracic junction are characterized by their unique location, complex anatomy and various histopathological subtypes. An individualized approach during surgery enhances safety and standardized of treatments for patients with tumours located at the cervicothoracic junction.
Cardiac surgery in older patients: hospital outcomes during a 15-year period from a complete national series
Authors: Jones James Mark , Loubani Mahmoud , Grant Stuart W , Goodwin Andrew T , Trivedi Uday , Kendall Simon , Jenkins David P
Published: October 2021

OBJECTIVES

The objective was to review national trends in activity and hospital outcomes in older patients having cardiac surgery over a 15-year time period.

METHODS

Data were collected prospectively and uploaded to the National Institute for Cardiovascular Outcomes Research electronically. Data were validated, cleaned and processed using reproducible algorithms. Mortality was death in hospital after index operation.

RESULTS

A total of 227 442 cardiac procedures were recorded in patients aged ≥70 years of which 46 354 were in those aged ≥80 years. Overall patients aged ≥70 years represented 43% of all adult cardiac surgery in the most recent study year. The annual proportion of surgery in patients ≥80 years increased from 4.1% to 10.8% between the first and last study years. There has been a significant linear increase in octogenarian valve [β 67.44, 95% confidence interval (CI) 55.04 to 79.83, P < 0.001] and coronary artery bypass graft surgery (β 32.53, 95% CI 6.16 to 58.90, P = 0.020) patients. In-hospital mortality reduced significantly for patients aged 70–79 years (β −0.17, 95% CI −0.20 to −0.13, P < 0.001) and all patients aged ≥80 (β −0.37, 95% CI −0.45 to −0.30, P < 0.001). The median length of hospital stay was 7 days for 70–79 and 9 days for ≥80 group, compared with 7 days for the whole cohort <70 years.

CONCLUSIONS

This study represents the largest complete validated national dataset of cardiac surgery in the entire population of older patients. Octogenarians represent 11% of adult patients having cardiac surgery by the end of the study period, a three-fold increase from the start. In-hospital mortality in patients aged ≥80 years halved during study period to only 4% despite high logistic EuroSCORE of 15%. Cardiac surgery in octogenarians places a higher demand on resources, however, with an increased postoperative length of stay.
Benzodiazepine and Z-Drug Use and the Risk of Developing Dementia
Authors: Torres-Bondia Francisco , Dakterzada Farida , Galván Leonardo , Buti Miquel , Besanson Gaston , Grill Eric , Buil Roman , de Batlle Jordi , Piñol-Ripoll Gerard
Published: October 2021

Background

Benzodiazepines (BZDs) and Z-drugs (BZDRs) are among the most prescribed medications for anxiety and insomnia, especially among older adults. Our objective was to investigate the association between the use of BZDRs and the risk of dementia.

Methods

A community-based retrospective cohort study was conducted based on the data available from 2002 to 2015 in Catalan Health Service. This cohort included all BZDR users (N = 83 138) and nonusers (N = 84 652) older than 45 years. A minimum 5-year lag window and an adjustment for psychiatric problems were applied for the data analysis.

Results

The hazard ratio (HR) for the risk of incident dementia among BZDR users was 1.22 (95% CI = 1.15 to 1.31). This risk was not significant after adjusting the data confounding factors (HR = 1.01; 95% CI = 0.94 to 1.08). We observed a higher risk with short-to-intermediate half-life BZDs (HR = 1.11; 95% CI = 1.04 to 1.20) and Z-drugs (HR = 1.20; 95% CI = 1.07 to 1.33) than for intermediate-to-long half-life BZDs (HR = 1.01; 95% CI = 0.94 to 1.08). We demonstrated a higher risk of incident dementia (HR = 1.23; 95% CI = 1.07 to 1.41 and odds ratio = 1.38; 95% CI = 1.27 to 1.50, respectively) in patients who received 91 to 180 defined daily doses (DDDs) and >180 DDDs compared with patients who received <90 DDD. Regarding patient sex, the risk of dementia was higher in women than in men.

Conclusion

We found that the incidence of dementia was not higher among all BZDR users. Short half-life BZDs and Z-drugs increased the risk of dementia at the highest doses, especially in female patients, showing a dose-response relationship.
BSAC Vanguard Series: Inequality and antibiotic resistance
Authors: Mendelson Marc
Published: October 2021

COVID-19 has highlighted the worldwide inequities in access to the tools needed to tackle the pandemic. The same is the case for antibiotic resistance (ABR), which is projected to cause far greater devastation. The truth is that unless we tackle the burden of infectious diseases in low- and middle-income countries (LMICs), we will not impact ABR worldwide. Despite valiant efforts we have largely failed to address antibiotic conservation. We have directed millions of dollars into developing new antibiotics and surveillance systems and mostly ignored interventions such as infection prevention. Insufficient resources are dedicated to interventions such as sanitation and clean water, vaccination and changes in agricultural practice to reduce reliance on antimicrobials. Large-scale public health interventions are required. Funding mechanisms must be found to support LMICs in making these changes. Action is required at the highest levels.
Chlorhexidine gluconate usage is associated with antiseptic tolerance in staphylococci from the neonatal intensive care unit
Authors: Sethi Dheeraj K , Felgate Heather , Diaz Maria , Faust Kirstin , Kiy Cemsid , Clarke Paul , Härtel Christoph , Rupp Jan , Webber Mark A
Published: October 2021

Background

Intravascular catheters are essential for care in Neonatal Intensive Care Units (NICUs) but predispose infants to catheter-associated infections including late-onset sepsis, commonly caused by CoNS. Antiseptics are applied to prevent infection with chlorhexidine (CHG) and octenidine (OCT) the most common agents used.

Objectives

To investigate the association between antiseptic use and bacterial susceptibility.

Methods

CoNS isolates were collected from two NICUs with differing antiseptic regimens: Norwich, UK (using CHG) and Lubeck, Germany (using OCT). CoNS were isolated from different body sites of babies upon admission, and weekly thereafter. Antiseptic susceptibility testing was performed, and a selection underwent genome sequencing.

Results

A total of 1274 isolates were collected. UK isolates (n = 863) were significantly less susceptible than German isolates (n = 411) to both CHG (mean MIC: 20.1 mg/L versus 8.9 mg/L) and OCT (mean MIC: 2.3 mg/L versus 1.6 mg/L). UK isolates taken on admission were more susceptible to CHG than subsequent isolates. No cross-resistance between the agents was seen. Genome sequencing of 122 CoNS showed the most common species to be Staphylococcus epidermidis and Staphylococcus haemolyticus and phylogenetic analysis suggested antiseptic tolerance evolved multiple times in independent lineages. There was no evidence of dominant antiseptic tolerant clones and carriage of genes previously implicated in antimicrobial susceptibility (qac, smr, norA/B), did not correlate with CHG or OCT susceptibility.

Conclusions

Long-term CHG use may select for CHG and OCT tolerance in CoNS. This highlights the different potential for separate antiseptic regimens to select for resistance development. This could be an important factor in developing future infection control policies.
Belief and Doubt in the Landscape and Holocaust Poems of David Fram (1903–88)
Authors: Frankel Hazel
Published: October 2021

This study of Lithuanian South African Yiddish poet David Fram foregrounds poems in which he wrestles with issues of belief, observance, abandonment, and doubt. It juxtaposes Fram’s nature poems with those that encompass the impact of the Holocaust from the viewpoint of a distant observer, written before, during, and after the Second World War. Close analysis of the poems’ lyrical forms highlights his deep emotional and spiritual connection to nature and gratitude towards the Creator, which may be considered pantheistic, in contrast with the challenges to his trust in the Jewish God and commitment to traditional observance during catastrophic times.
Dairy bioactive proteins and peptides: a narrative review
Authors: Auestad Nancy , Layman Donald K
Published: October 2021

Milk proteins are known for their high nutritional quality, based on their essential amino acid composition, and they exhibit a wide range of bioactivities, including satiety, antimicrobial, mineral-binding, and anti-lipidemic properties. Because of their unique water solubility, milk proteins are readily separated into casein and whey fractions, which can be further fractionated into many individual proteins, including alpha-S1- and alpha-S2-caseins, beta-casein, and kappa-casein, and the whey proteins alpha-lactalbumin, lactoferrin, beta-lactoglobulin, and glycomacropeptide. Many of these proteins have unique bioactivities. Further, over the past 30 years, peptides that are encrypted in the primary amino acid sequences of proteins and released along with amino acids during digestion are increasingly recognized as biologically active protein metabolites that may have beneficial effects on human health. This review examines the current state of the science on the contribution of dairy proteins and their unique peptides and amino acids to human health.
An Analysis of the Multidimensional Structure of Job Crafting for Older Workers With a Managerial Role
Authors: Vignoli Michela , Perinelli Enrico , Demerouti Evangelia , Truxillo Donald M
Published: October 2021

Job crafting has often been conceptualized as a higher-order construct composed of 3 dimensions: seeking resources, seeking challenges, and reducing demands. However, recent advances in job crafting studies have questioned the composition of its multidimensional structure. Furthermore, job crafting has been widely studied in age-diverse samples of workers, but not properly studied among older workers. In this article, we investigate the multidimensional structure of job crafting in 2 samples of older workers with a managerial role. In Study 1, in a cross-sectional sample (1,020 school superintendents, Mage = 57.27, SDage = 5.15) using a series of competing factorial analytic models (CFA, ESEM, bifactor-CFA, bifactor-ESEM), we demonstrated that reducing demands did not show significant relationships with the other 2 dimensions (at both the item and latent levels). In Study 2, a longitudinal study (350 school superintendents, Mage = 56.54, SDage = 5.11, Wave = 2, lag = 10 months), we further supported the structural results obtained in Study 1; furthermore, using a factorial cross-lagged panel model with 2 widely-accepted correlated constructs of job crafting (i.e., work engagement and emotional exhaustion), we again supported the independent nature of the reducing demands dimension, and we also showed the importance of seeking challenges. Indeed, the latter was a significant longitudinal predictor of work engagement, while all the other cross-lagged relationships were nonsignificant. Overall, our studies pose new questions about the structure of job crafting in older-worker populations.
Immune targeted therapy for diffuse large B cell lymphoma
Authors: Zheng Yaxin , Si Junqi , Yuan Tian , Ding Sa , Tian Chen
Published: October 2021

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is highly heterogeneous and invasive. Although the majority of DLBCL patients show a good response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment, approximately one-third of patients still have a poor prognosis. Many immune-targeted drugs, such as bispecific T-cell engagers and CAR T-cell therapy, have been proven effective for refractory and relapsed patients. This article reviews the progress of immune targeted therapy for DLBCL.
Using Rasch Analysis to Validate the Michigan Hand Outcomes Questionnaire from the Wrist and Radius Injury Surgical Trial
Authors: Jayaram Mayank , Wang, B.S. Chang , Shauver Melissa J. , Wang Lu , Chung Kevin C.
Published: October 2021

Background:

The Michigan Hand Outcomes Questionnaire is a patient-reported outcome measure that has been validated in many upper extremity disorders using classic test theory. Rasch measurement analysis is a rigorous method of questionnaire validation that offers several advantages over classic test theory and was used to assess the psychometric properties of the Michigan Hand Outcomes Questionnaire. This study used Rasch analysis to evaluate the questionnaire for distal radius fractures in older adults. The incidence and costs of distal radius fractures are rising, and reliable assessment tools are needed to measure outcomes in this growing concern.

Methods:

Rasch analysis was performed using 6-month assessment data from the Wrist and Radius Injury Surgical Trial. Each domain in the Michigan Hand Outcomes Questionnaire was independently analyzed for threshold ordering, person-item targeting, item fit, differential-item functioning, response dependency, unidimensionality, and internal consistency.

Results:

After collapsing disordered thresholds and removing any misfitting items from the model, five domains (Function, Activities of Daily Living, Work, Pain, and Satisfaction) demonstrated excellent fit to the Rasch model. The Aesthetics domain demonstrated high reliability and internal consistency but had poor fit to the Rasch model.

Conclusions:

Rasch analysis further supports the reliability and validity of using the Michigan Hand Outcomes Questionnaire to assess hand outcomes in older adults following treatment for distal radius fractures. Results from this study suggest that questionnaire scores should be interpreted in a condition-specific manner, with more emphasis placed on interpreting individual domain scores, rather than the summary Michigan Hand Outcomes Questionnaire score.
The Significance of LRDA With Bilateral Involvement Compared With GRDA on EEG in Critically Ill Patients
Authors: Fong Michael W. K. , Jadav Rakesh , Alzawahmah Mohamed , Hussein Omar M. , Gilmore Emily J. , Hirsch Lawrence J.
Published: October 2021

Purpose:

Lateralized rhythmic delta activity (LRDA) is highly associated with seizures but generalized rhythmic delta activity (GRDA; symmetric by definition) has no known seizure association. A subset of LRDA includes patterns that are “bilateral asymmetric LRDA” (LRDA-ba), falling between purely unilateral LRDA and GRDA. The significance of this finding has not been previously addressed.

Methods:

Clinical, EEG, and imaging findings were reviewed in all patients with >6 hours of continuous EEG and LRDA-ba between 2014 and 2019. They were compared with a control group of patients with GRDA, matched 1:1 for prevalence, duration, and frequency of the predominant rhythmic pattern.

Results:

Two hundred fifty-eight patients with LRDA-ba and 258 matched controls with GRDA were identified. Statistically significant findings included that patients with LRDA-ba were more likely to have presented with an ischemic stroke (LRDA-ba 12.4% vs. GRDA 3.9%) or subdural hemorrhage (8.9% vs. 4.3%); those with GRDA were more likely to have a metabolic encephalopathy (GRDA 10.5% vs. LRDA-ba 3.5%) or “altered mental state” without clear etiology (12.5% vs. 4.3%). Patients with LRDA-ba were significantly more likely to have a background EEG asymmetry (LRDA-ba 62.0% vs. GRDA 25.6%) or focal (arrhythmic) slowing (40.3% vs. 15.5%), and acute (65.5% vs. 46.1%) or focal (49.6% vs. 28.3%) abnormalities on computed tomography scan. Patients with LRDA-ba were more likely to have focal sporadic epileptiform discharges (95.4% vs. 37.9%), lateralized periodic discharges (32.2% vs. 5.0%), and focal electrographic seizures (33.3% vs. 11.2%); however, patients with LRDA-ba alone (i.e., without sporadic epileptiform discharges or PDs) showed only a trend toward increased seizures (17.3%) compared with a matched group of patients with GRDA alone (9.9%, P = 0.08).

Conclusions:

Patients with LRDA-ba had a higher proportion of acute focal abnormalities compared with a matched group of patients with GRDA. The LRDA-ba was associated with additional evidence of focal cortical excitability on EEG (sporadic epileptiform discharges and lateralized periodic discharges) and seizures but with only a trend toward increased seizures when other signs of focal excitability were absent.
Some rats take more time to make easier perceptual decisions
Authors: Reinagel Pamela
Published: October 2021

When subjects control the duration of sampling a sensory stimulus before making a decision, they generally take more time to make more difficult sensory discriminations. This has been found to be true of many rats performing visual tasks. But two rats performing visual motion discrimination were found to have inverted chronometric response functions: their average response time paradoxically increased with stimulus strength. We hypothesize that corrective decision reversals may underlie this unexpected observation.
Artificial intelligence reveals nuclear pore complexity
Authors: Mosalaganti Shyamal , Obarska-Kosinska Agnieszka , Siggel Marc , Turonova Beata , Zimmerli Christian E. , Buczak Katarzyna , Schmidt Florian H. , Margiotta Erica , Mackmull Marie-Therese , Hagen Wim , Hummer Gerhard , Beck Martin , Kosinski Jan
Published: October 2021

Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport. Their intricate 120 MDa architecture remains incompletely understood. Here, we report a near-complete structural model of the human NPC scaffold with explicit membrane and in multiple conformational states. We combined AI-based structure prediction with in situ and in cellulo cryo-electron tomography and integrative modeling. We show that linker Nups spatially organize the scaffold within and across subcomplexes to establish the higher-order structure. Microsecond-long molecular dynamics simulations suggest that the scaffold is not required to stabilize the inner and outer nuclear membrane fusion, but rather widens the central pore. Our work exemplifies how AI-based modeling can be integrated with in situ structural biology to understand subcellular architecture across spatial organization levels.

One sentence summary

An AI-based, dynamic model of the human nuclear pore complex reveals how the protein scaffold and the nuclear envelope are coupled inside cells.
Experience-induced remodeling of the hippocampal post-synaptic proteome and phosphoproteome
Authors: Heo Seok , Kang Taewook , Bygrave Alexei M. , Larsen Martin R. , Huganir Richard L.
Published: October 2021

The post synaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the PSD proteome and phosphoproteome in mice following various treatments. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated for quantitative proteomic and phosphoproteomics analysis. We used a sequential enrichment strategy to explore the concurrent events of protein expression and phosphorylation in the hippocampal PSD following IA training (IA) or immediate shock (Shock). We identified more than 6,200 proteins and 3,000 phosphoproteins in the sequential strategy covering a total of 7,429 proteins. On the phosphoproteins we identified a total of 9,589 phosphosites. Strikingly, of the significantly IA-regulated proteins and phosphoproteins, a large fraction of the proteins displayed an overall decrease in phosphorylation level. Bioinformatic analysis of proteins and phosphoproteins that were regulated by IA were annotated for an involvement in regulation of glutamate receptor functionality, calcium signaling, and synaptic plasticity. We also identified synaptic kinases, phosphatases and their respective phosphosites regulated by IA training or immediate shock. Furthermore, we found that AMPA receptor surface expression was regulated by protein phosphatase, Mg2+/Mn2+ dependent 1H (Ppm1h). Together, these results unravel the dynamic remodeling of the PSD upon IA learning or immediate shock and serve as a resource for elucidating the synaptic proteome dynamics induced by experience-dependent plasticity.

Highlights

The proteome and phosphoproteome of mouse hippocampal PSD fractions were examined using quantitative phosphoproteomics and bioinformatics following inhibitory avoidance training or non-associative immediate shock.

Approximately 6,200 proteins and 3,000 phosphoproteins were identified and quantified in the hippocampal PSD fractions.

IA mediates widespread decreases in the abundance and phosphorylation of proteins in the hippocampal PSD fraction.

Kinases, phosphatases and their phosphorylation status were dynamically and significantly regulated by IA and immediate shock.

Functional validation shows that the protein phosphatase Ppm1h is linked to the regulation of synaptic plasticity in vitro and in vivo.

In Brief

Quantitative proteomics and phosphoproteomics combined with subcellular protein fractionation and bioinformatic analysis identifies a highly dynamic regulation of synaptic protein phosphorylation at the postsynaptic density following IA training and immediate shock.
Altered circadian rhythms and sleep in a new Angelman Syndrome mouse model
Authors: Shi Shu-qun , Mahoney Carrie E. , Houdek Pavel , Zhao Wenling , Anderson Matthew P. , Zhuo Xinming , Beaudet Arthur , Sumova Alena , Scammell Thomas E. , Johnson Carl Hirschie
Published: October 2021

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a down-regulation (models of Angelman syndrome) vs. Ube3a up-regulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. In contrast to previous reports, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei, the pacemaking circadian brain locus. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.
CaPti1/CaERF4 module positively regulates pepper resistance to bacterial wilt disease through coupling enhanced immunity and dehydration tolerance
Authors: Shi Lanping , Li Xia , Weng Yahong , Cai Hanyang , Liu Kaisheng , Xie Baixue , Ansar Hussain , Guan Deyi , He Shuilin , Liu Zhiqin
Published: October 2021

Bacterial wilt, a severe disease that affects over 250 plant species, is caused byRalstonia solanacearumthrough vascular system blockade. Although both plant immunity and dehydration tolerance might contribute to disease resistance, whether and how they are related are still unclear. Herein, we provide evidence that immunity againstR. solanacearumand dehydration tolerance are coupled and regulated byCaPti1-CaERF4 module. By expression profiling, virus-induced gene silencing in pepper and overexpression inNicotiana benthamiana, bothCaPti1andCaERF4were upregulated byR. solanacearuminoculation, dehydration stress and exogenously applied ABA. They in turn phenocopied with each other in promoting pepper resistance to bacterial wilt not only by activating HR cell death and SA-dependentCaPR1, but also by activating dehydration tolerance relatedCaOSM1andCaOSR1, and stomata closure to reduce water loss in ABA signaling dependent manner. Yeast-two hybrid assay showed thatCaERF4 interacts withCaPti1, which was confirmed by co-immunoprecipitation and pull-down assays. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that, uponR. solanacearuminoculation,CaPR1, CaOSM1andCaOSR1were directly targeted and positively regulated byCaERF4 via binding GCC-box or DRE-box, which was potentiated byCaPti1. In addition, our data indicate thatCaPti1-CaERF4 complex might act downstream ABA signaling, since the exogenously applied ABA did not alter stomata aperture regulated byCaPti1-CaERF4 module. Importantly,CaPti1-CaERF4 module was found also acts positively in pepper growth and response to dehydration stress. Collectively, the results suggest that immunity and dehydration tolerance are coupled and positively regulated byCaPti1-CaERF4 in pepper plants to enhance resistance againstR. solanacearum.

Pepper immunity and dehydration tolerance are coupled and regulated by theCaPti1-CaERF4 module partially in a way related to ABA signaling and stomata closure.
A cautionary tale on proper use of branch-site models to detect convergent positive selection
Authors: Kowalczyk Amanda , Chikina Maria , Clark Nathan L
Published: October 2021

Comparative genomics has become a powerful tool to elucidate genotype-phenotype relationships, particularly through the study of convergently acquired phenotypes. By identifying genes under positive selection specifically on branches with the convergent phenotype we can potentially link genes to that phenotype. Such gene scans are often done using branch-site codon models. However, we have observed a recent troubling trend of misinterpretation of branch-site models in which phylogeny-wide positive selection is not distinguished from positive selection specific to convergent branches. Here, we use simulations and real data to demonstrate how failing to discern between these two cases leads to false inferences of positive selection associated with a convergent trait. We then present a “ drop-out” test solution to distinguish the two cases and thereby truly capture positive selection events associated with convergent phenotypes, thus allowing for further insights into both genetic and phenotypic evolution.
Aging decreases the lateralization of gravity-related effort minimization during vertical arm movements
Authors: Poirier Gabriel , Papaxanthis Charalambos , Lebigre Mélanie , Juranville Adrien , Mathieu Robin , Savoye-Laurens Timothée , Manckoundia Patrick , Mourey France , Gaveau Jeremie
Published: October 2021

Motor lateralization refers to differences in the neural organization of cerebral hemispheres, resulting in different control specializations between the dominant and the non-dominant motor systems. Multiple studies proposed that the dominant hemisphere is specialized for open-loop optimization-like processes. Recently, comparing arm kinematics between upward and downward movements, we found that the dominant arm outperformed the non-dominant one regarding gravity-related motor optimization in healthy young participants. The literature about aging effects on motor control presents several neurophysiological and behavioral evidences for an age-related reduction of motor lateralization. Here, we compare the lateralization of a well-known gravity-related optimal motor control process between young and older adults. Forty-one healthy young (mean age = 24.3 ± 3 years) and forty-two healthy older adults (mean age = 72.0 ± 6 years) performed single degree-of-freedom vertical arm movements between two targets (upward and downward). Participants alternatively reached with their dominant and non-dominant arms. We recorded arm kinematics and electromyographic activities of the prime movers (Anterior and Posterior Deltoids) and we analyzed parameters thought to represent the hallmark of the gravity-related optimization process (i.e directional asymmetries and negative epochs on the phasic EMG activity). We found strong age x arm interaction effects on all parameters; i.e., relative durations to peak acceleration and peak velocity and the negativity of antigravity muscles’ phasic signals. Although all three parameters showed a lateralization effect where the dominant arm was superior to the non-dominant arm in young adults (as in Poirier et al. 2022), we found no such effect in older adults. With both arms, the results of older adults lied between those of the dominant and non-dominant arm of young adults. These results add to those of recent literature showing that feedforward motor control remains functional in older adults. More, the results obtained with the non-dominant arm may support a previously hypothesized increased reliance on predictive mechanisms in older adults.
The hormone Fibroblast Growth Factor 19 stimulates water intake
Authors: Ursic-Bedoya José , Chavey Carine , Meunier Lucy , Desandré Guillaume , Dupuy Anne-Marie , Reyes Iria Gonzalez-Dopeso , Tordjmann Thierry , Assénat Eric , Hibner Urszula , Gregoire Damien
Published: October 2021

Fibroblast growth factor 19 (FGF19) is a hormone with pleiotropic metabolic functions, leading to ongoing development of analogues for the treatment of metabolic disorders. On the other hand, FGF19 is overexpressed in a sub-group of hepatocellular carcinoma (HCC) patients and has oncogenic properties. It is therefore crucial to precisely define FGF19 effects, notably chronic exposure to elevated concentrations of the hormone. We used hydrodynamic gene transfer approach to generate a transgenic mouse model with long-term FGF19 hepatic overexpression. Here we describe a novel effect of FGF19, namely stimulation of water intake. This phenotype, lasting at least over a 6-month period, depends on signaling in the central nervous system and is independent of FGF21, although it mimics some of its features. We further show that HCC patients with high levels of circulating FGF19 have a reduced natremia, indicating dispogenic features. The present study provides evidence of a new activity for FGF19, which could be clinically relevant in the context of FGF19 overexpressing cancers and treatment of metabolic disorders by FGF19 analogues.
Diversity analysis of soil microbial population abundance before and after planting JunCao “Oasis No. 1” in saline-alkali soil
Authors: Zhi Qi Xiao , Zhan Xi Lin
Published: October 2021

In order to explore the difference of soil microbial population structure and abundance before and after planting JunCao “Oasis No. 1” in saline-alkali soil, verify the improvement effect of JunCao “Oasis No. 1” on microbial population structure and abundance in saline-alkali soil. Samples were collected from the blank saline area with and without JunCao “Oasis NO.1” and no plant growth on the surface, respectively, as Experimental group soil samples (S.Y.1-S.Y.8) and Blank group soil samples (K.B.1-K.B.8).16sDNA high-throughput sequencing technology was used for sequencing analysis respectively, and the diversity of microbial population abundance between them was compared and analyzed.The results showed that the diversity of microbial population abundance in the experimental group was significantly higher than that in the blank group, and the diversity of microbial population abundance in the experimental group was significantly different from that in the blank group, indicating that the composition of microbial population in the experimental group was significantly different from that in the blank group. In the OTU cluster analysis, the number of OTU clusters in the Experimental group soil samples (S.Y.1-S.Y.8) was significantly higher than that in the Blank group soil samples (K.B.1-K.B.8). In the sample complexity analysis of α-diversity analysis, the richness and diversity of microbial population in soil samples of Experimental group (S.Y.1-S.Y.8) were significantly higher than that in soil samples of Blank group (K.B.1-K.B.8), which was clearly reflected in the Species accumulation boxplot and Graph of species diversity. In the β-diversity analysis, PcoA, PCA and NMDS analysis methods were used to analyze the difference of microbial population diversity between Experimental soil samples (S.Y.1-S.Y.8) and Blank soil samples (K.B.1-K.B.8). The results showed that the diversity of microbial population in Experimental soil sample (S.Y.1-S.Y.8) was significantly different from that in Blank soil sample (K.B.1-K.B.8). In this paper, 16sDNA high-throughput sequencing technology was used to analyze the diversity of microbial population abundance between Blank soil samples and Experimental soil samples, and it was proved that JunCao “Oasis No. 1” had good saline-alkali soil improvement characteristics. It can effectively increase the abundance of microbial population in saline-alkali soil, so as to restore the microbial population ecosystem in saline-alkali soil, which has important application value in soil saline-alkali control.
Characterising severe traumatic brain injury from fresh cerebral biopsy in living patients
Authors: Yip Ping K. , Hasan Shumaila , Uff Christopher E.G.
Published: October 2021

Traumatic brain injury (TBI) is one of the most complex disorder in the most complex organ in the body and current classifications of mild, moderate and severe often fail to capture this complexity. Although the mainstay of prognosis involves several clinical classification systems, these systems are confined to macroscopic analysis. Therefore, we aim to use immunohistochemical examination of fresh brain biopsy samples to study the cellular and molecular changes caused by severe TBI.

Twenty-five adult patients suffering severe TBI were recruited into the Severe Head Injury Brain Analysis (SHIBA) study. Fresh brain biopsies obtained prior intracranial pressure (ICP) monitor insertion or during craniotomy underwent immunohistochemical analysis using the neuronal marker (NeuN), dendritic marker (MAP2), vascular markers (claudin-5 and vWF), and neuroinflammation markers (Iba1 and P2Y12) to investigate the injury severity at microscopic level.

Obtaining brain biopsy from the twenty-five patients in the study did not cause any additional burden to patient’s standard care and there were no adverse effects. The mean (± SD) Glasgow Outcome Scale-Extended (GOS-E) 3-months after injury was 4.0 (± 2.7), consisting of 64% unfavourable outcomes and 36% favourable outcomes. Immunostaining of brain tissue revealed various qualitative changes resulting in neuronal injury, dendritic injury, neurovascular injury, and neuroinflammation, which we classified into 4 subgroups for each injury type using the newly devised Yip, Hasan and Uff (YHU) grading system. Using this grading scale, patients with a total YHU grade of ≥ 11, 100% (n=11) had a GOS-E of ≤ 4, including death (54.5%), vegetative state (18.2%) and severe disability (27.3%) 3-months post injury. In contrast, those with a YHU grade of ≤ 8, 100% (n=8) had a GOS-E of 5 or higher, indicating a favourable outcome. Linear regression showed a significant negative correlation between the GOS-E and neuronal injury (R2 =0.240, p= 0.0129), dendritic injury (R2 =0.430, p= 0.0004), neurovascular injury (R2 =0.538, p<0.0001), and neuroinflammation (R2 =0.361, p= 0.0015).

Brain biopsy in severe TBI is a simple and safe procedure. Furthermore, immunofluorescence staining enables classification of this heterogeneous patient population into various categories of injury severity based on the cellular and molecular pathophysiology according to the YHU grading system. This new grading scale should facilitate a more precise diagnosis, similar to what is currently standard in oncology, allowing earlier and more accurate prognosis than current grading systems, thereby adding to the arsenal of resources available to guide clinical decision making in treating patients with severe TBI.
Conscious processing of global and local auditory irregularities causes differentiated heartbeat-evoked responses
Authors: Candia-Rivera Diego , Raimondo Federico , Pérez Pauline , Naccache Lionel , Tallon-Baudry Catherine , Sitt Jacobo D.
Published: October 2021

Recent research suggests that brain-heart interactions are associated with perceptual and self-consciousness. In this line, the neural responses to visceral inputs have been hypothesized to play a leading role in shaping our subjective experience. This study aims to investigate whether the contextual processing of auditory irregularities modulates both direct neuronal responses to the auditory stimuli (ERPs) and the neural responses to heartbeats, as measured with heartbeat-evoked responses (HERs). HERs were computed in patients with disorders of consciousness, diagnosed with a minimally conscious state or unresponsive wakefulness syndrome. We tested whether HERs reflect conscious auditory perception, which can potentially provide additional information for the consciousness diagnosis. EEG recordings were taken during the local-global paradigm, which evaluates the capacity of a patient to detect the appearance of auditory irregularities at local (short-term) and global (long-term) levels. The results show that local and global effects produce distinct ERPs and HERs, which can help distinguish between the minimally conscious state and unresponsive wakefulness syndrome patients. Furthermore, we found that ERP and HER responses were not correlated suggesting that independent neuronal mechanisms are behind them. These findings suggest that HER modulations in response to auditory irregularities, especially local irregularities, may be used as a novel neural marker of consciousness and may aid in the bedside diagnosis of disorders of consciousness with a more cost-effective option than neuroimaging methods.
The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study
Authors: Lim Qui-Yi , Taylor Kurt , Dudding Tom
Published: October 2021

Objectives

Explore associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).

Use negative control analyses to explore for the presence of confounding.

Methods

Using prospectively collected data from Avon Longitudinal Study of Parents and Children (ALSPAC), we performed logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We compared these with negative control exposure (paternal BMI, smoking and alcohol) and outcome (offspring dental trauma) analyses.

Results

5,536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a weak, positive association between maternal mean BMI and offspring MIH (OR per 1□kg/m2 difference in BMI: 1.04, 95%CI: 1.00, 1.08). Results of subsequent analyses suggested this effect was non-linear and being driven by women in the highest BMI quintile (OR for women in the highest BMI quintile versus the lowest: 1.61 95%CI: 1.02, 2.60). Negative control analyses showed no evidence of an association between paternal BMI and offspring MIH (OR: 0.94, 95%CI: 0.89,1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95%CI: 0.96, 1.02). There was no clear evidence of an association for maternal smoking (OR: 0.76, 95%CI: 0.46,1.22) or alcohol consumption (OR: 0.79, 95%CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

Conclusion

We found evidence of a possible intrauterine effect for high maternal pre-pregnancy BMI on offspring MIH, but no robust evidence of an intrauterine effect for maternal pregnancy smoking or alcohol consumption. A key limitation includes possible misclassification of MIH. Replication of these results is warranted.