bluuebunny/crossref_metadata_2025 huggingface dataset:
Neospora caninum Evades Immunity via Inducing Host Cell Mitophagy to Inhibit Production of Proinflammatory Cytokines in a ROS-Dependent Manner
Authors: Zhang Xu , Wang Yuru , Gong Pengtao , Wang Xiaocen , Zhang Nan , Chen Mengge , Wei Ran , Zhang Xichen , Li Xin , Li Jianhua
Published: March 2022

Neospora caninum is an intracellular protozoan that mainly infects cattle to cause abortion and significant economic losses worldwide. A better understanding of the immune evasion mechanisms of N. caninum could help to search for an effective approach to prevent and treat neosporosis. Mitophagy is used by some viruses to evade host immune surveillance. However, host cell mitophagy and its effect on N. caninum infection is unclear. In the present study, N. caninum-induced host cell mitophagy and its role in parasite infection were investigated in vitro and in vivo. Furthermore, the regulation of N. caninum-induced host cell mitophagy on the production of Reactive Oxygen Species (ROS), the secretions of proinflammatory cytokines, and the signals of p38, ERK, and Nlrp3 inflammasome were explored. Our results showed that autophagosomes and co-localization of LC3 with mitochondria were observed in N. caninum-infected macrophages. The mtDNA/nDNA ratio and the levels of mitochondrial marker proteins (Hsp60 and Tim23) were decreased with the increase of N. caninum numbers or infection time. N. caninum could induce mitophagy in brain and peritoneal lavage fluid cells of mice. Promoting mitophagy via mitophagy inducers (CCCP) could shorten survival time, decrease body weight, increase parasite load, and attenuate secretion of cytokines in N. caninum infected mice. CCCP treatment decreased the production of cytokines and Reactive Oxygen Species (ROS), and increased parasite burden in N. caninum-infected macrophages. Furthermore, CCCP or NAC (ROS inhibitor) treatment could inhibit ERK signal, Nlrp3 inflammasome, and cytokine production, while promote p38 signal in N. caninum-infected macrophages. The opposite results were obtained when using a mitophagy inhibitor (Mdivi1). Taken together, N. caninum-induced mitophagy could regulate the activations of p38, ERK, Nlrp3 inflammasome to inhibit the production of inflammatory cytokines in a ROS-dependent manner to escape host immune surveillance.
Angiotensin-(1–7) as a Potential Therapeutic Strategy for Delayed Cerebral Ischemia in Subarachnoid Hemorrhage
Authors: Annoni Filippo , Moro Federico , Caruso Enrico , Zoerle Tommaso , Taccone Fabio Silvio , Zanier Elisa R.
Published: March 2022

Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin–angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor AT1R, and a counterbalancing system, presented in humans as Ang-(1–7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1–7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson’s disease, and depression. In the presence of SAH, Ang-(1–7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1–7).
Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets
Authors: Zhang Yan , Khan Suliman , Liu Yang , Wu Guofeng , Yong V. Wee , Xue Mengzhou
Published: March 2022

Intracerebral hemorrhage (ICH) is a highly fatal disease with mortality rate of approximately 50%. Oxidative stress (OS) is a prominent cause of brain injury in ICH. Important sources of reactive oxygen species after hemorrhage are mitochondria dysfunction, degradated products of erythrocytes, excitotoxic glutamate, activated microglia and infiltrated neutrophils. OS harms the central nervous system after ICH mainly through impacting inflammation, killing brain cells and exacerbating damage of the blood brain barrier. This review discusses the sources and the possible molecular mechanisms of OS in producing brain injury in ICH, and anti-OS strategies to ameliorate the devastation of ICH.
T-Cell Responses to Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses to the Colorectal Cancer Antigen, Guanylyl Cyclase C
Authors: Flickinger John C. , Singh Jagmohan , Yarman Yanki , Carlson Robert D. , Barton Joshua R. , Waldman Scott A. , Snook Adam E.
Published: March 2022

The Gram-positive bacteriumListeria monocytogenes(Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C vaccine previously shown to induce robust GUCY2C254-262immunity completely suppressed GUCY2C254-262responses. Comparison of immunogenic Lm-derived peptides to GUCY2C254-262revealed that Lm-derived peptides form highly stable peptide-MHC complexes with H-2Kdcompared to GUCY2C254-262peptide. Moreover, amino acid substitution at a critical anchoring residue for H-2Kdbinding, producing GUCY2CF255Y, significantly improved stability with H-2Kdand rescued GUCY2C254-262immunogenicity in the context of Lm vaccination. Collectively, these studies suggest that Lm antigens may compete with and suppress the immunogenicity of target vaccine antigens and that use of altered peptide ligands with enhanced peptide-MHC stability may be necessary to elicit robust immune responses. These studies suggest that optimizing target antigen competitiveness with Lm antigens or alternative immunization regimen strategies, such as prime-boost, may be required to maximize the clinical utility of Lm-based vaccines.
Oyster Reef Surfaces in the Central Wadden Sea: Intra-Reef Classification and Comprehensive Statistical Description
Authors: Hitzegrad Jan , Brohmann Leon , Pfennings Kai , Hoffmann Tom K. , Eilrich Anne K. , Paul Maike , Welzel Mario , Schlurmann Torsten , Aberle Jochen , Wehrmann Achim , Goseberg Nils
Published: March 2022

The Pacific oyster (Magallana gigas) is an invasive species in the Wadden Sea transforming parts of it permanently. M. gigas, as an ecosystem engineer, builds reef structures that are characterized by highly complex and variable surfaces consisting of densely packed, sharp-edged individuals connected with cement-like bonds. To investigate the interactions between reef structure, shape and formation and wave as well as tidal currents, an understanding of the surface roughness is essential. This work reports on observations of oyster reefs for which seven new structural classes (Central Reef, Transitional Zone, Cluster I, Cluster II, Patch I, Patch II, and Garland) are proposed. For each class, high resolution Digital Elevation Models (DEMs) have been elaborated based on Structure-from-Motion (SfM) photogrammetry and analyzed using spatial statistics. By determining probability density functions (PDFs), vertical porosity distributions, abundances, orientations and second-order structure functions (SSFs), topographical parameters that influence the hydraulic bed roughness have been determined. The results suggest, that by applying the structural classification and their distinct topographical roughness parameters, the oyster reef surfaces can be described appropriately accounting for their complexity. The roughness accounts to a total roughness height kt = 103 ± 15 mm and root-mean-square roughness height krms = 23 ± 5 mm. These values were found similar across all structural classes, yet the shape of the PDFs reveal differences. With decreasing abundance, the distributions become more positively skewed and are characterized by more extreme outliers. This is reflected in the higher statistical moments, as the skewness ranges between Sk = 0.4–2.1 and the kurtosis between Ku = 2.2–11.5. The analysis of the orientations and the SSFs confirms anisotropic behavior across all structural classes. Further, the SSFs reveal the oyster shells as significant roughness elements with exception of Cluster I and II, where the clusters are identified as significant roughness elements. The provided set of topographical roughness parameters enhances the knowledge of oyster reef surfaces and gives insights into the interactions between biogenic structure and surrounding hydrodynamics. The new intra-reef classification allows for more accurate determination of the overall roughness as well as the population dynamics of the habitat forming oyster. Combined with hydraulic measurements, the results can be used to estimate the hydraulic bed roughness induced by the oyster reef surfaces.
Pneumocystis Jirovecii Pneumonia Diagnosis via Metagenomic Next-Generation Sequencing
Authors: Lu Xiaoxiao , Zhang Jianhui , Ma Wentao , Xing Lihua , Ning Hanbing , Yao Mengying
Published: March 2022

The incidence of non-HIV-infected Pneumocystis Jirovecii Pneumonia (PJP) is increasing. The prognosis for non-HIV PJP is poor and diagnostic tests are of lower sensitivity in non-HIV patients. Metagenomic next-generation sequencing (mNGS) was compared with routine detection assays, including Gomori methenamine silver (GMS) stain and polymerase chain reaction (PCR) technique. Specimens of 4 bronchoalveolar lavages (BAL) and 1 lung tissue samples were obtained from 4 non-HIV patients from our hospitals. Although both GMS and mNGS were positive for P. jirovecii with PCR as positive control, the testing time of mNGS was obviously shorter than GMS. Compared with the traditional GMS method, mNGS has absolute advantages. However, the issue with PJP presentations having atypical symptoms and ambiguous imaging features persists. Hence, the disease can easily be ignored. Secondly, PJP progresses rapidly in non-HIV-infected patients and can cause severe respiratory failure with unfavorable prognosis. This study affirms that mNGS can be used to quickly and accurately diagnose PJP, but a combination of clinical judgement of symptoms, laboratory testing, and imaging examination is required to make a comprehensive judgment along with mNGS test results.
Regulatory Information and Guidance on Biosimilars and Their Use Across Europe: A Call for Strengthened One Voice Messaging
Authors: Barbier Liese , Mbuaki Allary , Simoens Steven , Declerck Paul , Vulto Arnold G. , Huys Isabelle
Published: March 2022

Background

Beyond evaluation and approval, European and national regulators have a key role in providing reliable information on biosimilars and the science underpinning their development, approval, and use.

Objectives

This study aims to (i) review biosimilar information and guidance provided by EMA and national medicines agencies and (ii) explore stakeholder perspectives on the role of regulators in enabling acceptance and use of biosimilars.

Methods

This study consists of (i) a comparative review of regulatory information and position statements across medicine agencies (n = 32) and (ii) qualitative interviews with stakeholders in Europe (n = 14).

Results

The comparative analysis showed that regulatory information and guidance about biosimilars offered by national medicines agencies in Europe varies, and is limited or absent in multiple instances. Approximately 40% (13/31) of the national medicines agencies' websites did not offer any information regarding biosimilars, and for about half (15/31) no educational materials were provided. Only less than half of national medicines agencies provided guidance on biosimilar interchangeability and switching (8/31 and 12/31, respectively). Among the national medicines agencies that did offer guidance, the extent (e.g., elaborate position vs. brief statement) and content (e.g., full endorsement vs. more cautious) of the guidance differed substantially. Countries that have a strong involvement in EU level biosimilar regulatory activities generally had more elaborate information nationally. Interviewees underwrote the need for (national) regulators to intensify biosimilar stakeholder guidance, especially in terms of providing clear positions regarding biosimilar interchangeability and switching, which in turn can be disseminated by the relevant professional societies more locally.

Conclusion

This study revealed that, despite strong EU-level regulatory biosimilar guidance, guidance about biosimilars, and their use differs considerably across Member States. This heterogeneity, together with the absence of a clear EU-wide position on interchangeability, may instill uncertainty among stakeholders about the appropriate use of biosimilars in practice. Regulators should strive for a clear and common EU scientific position on biosimilar interchangeability to bridge this gap and unambiguously inform policy makers, healthcare professionals, and patients. Furthermore, there is a clear opportunity to expand information at the national level, and leverage EU-developed information materials more actively in this regard.
Identification of the Genes of the Plant Pathogen Pseudomonas syringae MB03 Required for the Nematicidal Activity Against Caenorhabditis elegans Through an Integrated Approach
Authors: Ali Muhammad , Gu Tong , Yu Xun , Bashir Anum , Wang Zhiyong , Sun Xiaowen , Ashraf Naeem Mahmood , Li Lin
Published: March 2022

Nematicidal potential of the common plant pathogen Pseudomonas syringae has been recently identified against Caenorhabditis elegans. The current study was designed to investigate the detailed genetic mechanism of the bacterial pathogenicity by applying comparative genomics, transcriptomics, mutant library screening, and protein expression. Results showed that P. syringae strain MB03 could kill C. elegans in the liquid assay by gut colonization. The genome of P. syringae MB03 was sequenced and comparative analysis including multi locus sequence typing, and genome-to-genome distance placed MB03 in phylogroup II of P. syringae. Furthermore, comparative genomics of MB03 with nematicidal strains of Pseudomonas aeruginosa (PAO1 and PA14) predicted 115 potential virulence factors in MB03. However, genes for previously reported nematicidal metabolites, such as phenazine, pyochelin, and pyrrolnitrin, were found absent in the MB03 genome. Transcriptomics analysis showed that the growth phase of the pathogen considerably affected the expression of virulence factors, as genes for the flagellum, glutamate ABC transporter, phoP/phoQ, fleS/fleR, type VI secretion system, and serralysin were highly up-regulated when stationary phase MB03 cells interacted with C. elegans. Additionally, screening of a transposon insertion mutant library led to the identification of other nematicidal genes such as acnA, gltP, oprD, and zapE. Finally, the nematicidal activity of selected proteins was confirmed by heterologous expression in Escherichia coli.
Fate of Antibiotic Resistance Genes and Changes in Bacterial Community With Increasing Breeding Scale of Layer Manure
Authors: Wang Lixiao , Chai Baofeng
Published: March 2022

The use of antimicrobials in intensive poultry production is becoming increasingly common because of its high throughput of meat and egg products. However, the profile of antibiotic resistance genes (ARGs) and the underlying mechanisms in different breeding scale farms were not fully explored. The study examined the profiles of ARGs in layer manure from three free-range and 12 intensive layer farms with different scales (N500, N5000, N10000, and N20000). A quantitative PCR (qPCR) array was used to quantify ARGs, and microbial community structure was analyzed by 16S rRNA gene sequencing. A total of 48 ARGs, belonging to seven major types, were identified in the layer manure samples, with sul2, tetM-01, and ermB being the predominant ones. The abundance, diversity, and mobility potential of ARGs in layer manure changed significantly with the increasing of the breeding scale. The abundances of total ARGs had significantly positive correlations with mobile genetic elements (MGEs), suggesting the mobility potential of ARGs in layer manure samples. Bacterial abundance did not show significant differences among the five group manure samples. However, bacterial diversity showed an increasing trend along the breeding scale. Pathogenic Bacteroidetes increased in the largest-scale layer manure samples and showed significant positive correlations with most ARGs. Network analysis revealed significant co-occurrence patterns between ARGs and microbial taxa, indicating ARGs had a wide range of bacterial hosts. Proteobacteria and Firmicutes were potential hosts for tetracycline and macrolide-lincosamide-streptogramin B (MLSB) resistant genes. Our results indicated that the expansion of the breeding scale of a farm promotes the abundance, diversity, and mobility potential of ARGs in layer manure.
The Effect of Trustor Age and Trustee Age on Trustworthiness Judgments: An Event-Related Potential Study
Authors: Chen Zi-wei , Li Yong-na , Wang Ke-xin , Qi Yue , Liu Xun
Published: March 2022

Perceived trustworthiness based on facial appearance plays an important role in interpersonal trust and cooperative behavior. Interpersonal trust behaviors involve both trustors and trustees. However, there is no clear conclusion on how the age of the two individuals affects interpersonal trust behaviors. Therefore, this study used the trust game task to explore the differences in trust behaviors between two different age groups in response to faces of different ages and analyzed whether such differences were apparent in the face processing stage. The behavioral results showed that only younger adults invested more money with older partners than younger ones; that is, younger adults trusted older faces more. The event-related potential (ERP) analyses showed that in the early stage of face processing, younger faces elicited more negative N170 than older faces; at the same time, older faces elicited more positive VPP than younger faces, and younger adults had more positive VPP than older adults. In the middle and late stages of face processing, younger faces elicited more negative FRN than older faces in younger adults but not in older adults. In addition, older faces elicited more positive LPP than younger faces in older adults but not in younger adults. The neural analyses suggested that age-related differences in facial trustworthiness judgments might occur in the later stages of face processing. Combining the behavioral and neural results, we found a dissociation between trustworthiness perceptions and trust behaviors in both younger and older adults, which may provide insight into how to prevent older adults from being deceived.
Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis
Authors: Xu Jinling , Zhou Hui , Xiang Guangda
Published: March 2022

Background

Given the arrival of the aging population has caused a series of social and economic problems, we aimed to explore the key genes underlying cognitively normal brain aging and its potential molecular mechanisms.

Methods

GSE11882 was downloaded from Gene Expression Omnibus (GEO). The data from different brain regions were divided into aged and young groups for analysis. Co-expressed differentially expressed genes (DEGs) were screened. Functional analysis, protein–protein interaction (PPI) network, microRNA (miRNA)-gene, and transcription factor (TF)-gene networks were performed to identify hub genes and related molecular mechanisms. AlzData database was used to elucidate the expression of DEGs and hub genes in the aging brain. Animal studies were conducted to validate the hub genes.

Results

Co-expressed DEGs contained 7 upregulated and 87 downregulated genes. The enrichment analysis indicated DEGs were mainly involved in biological processes and pathways related to immune-inflammatory responses. From the PPI network, 10 hub genes were identified: C1QC, C1QA, C1QB, CD163, FCER1G, VSIG4, CD93, CD14, VWF, and CD44. CD44 and CD93 were the most targeted DEGs in the miRNA-gene network, and TIMP1, HLA-DRA, VWF, and FGF2 were the top four targeted DEGs in the TF-gene network. In AlzData database, the levels of CD44, CD93, and CD163 in patients with Alzheimer’s disease (AD) were significantly increased than those in normal controls. Meanwhile, in the brain tissues of cognitively normal mice, the expression of CD44, CD93, and CD163 in the aged group was significantly lower than those in the young group.

Conclusion

The underlying molecular mechanisms for maintaining healthy brain aging are related to the decline of immune-inflammatory responses. CD44, CD93, and CD 163 are considered as potential biomarkers. This study provides more molecular evidence for maintaining cognitively normal brain aging.
Risk of Dementia or Cognitive Impairment in Sepsis Survivals: A Systematic Review and Meta-Analysis
Authors: Lei Siyuan , Li Xuanlin , Zhao Hulei , Feng Zhenzhen , Chun Liu , Xie Yang , Li Jiansheng
Published: March 2022

Background

There is growing evidence that sepsis survivors are at increased risk of developing new-onset atrial fibrillation, acute kidney injury, and neurological diseases. However, whether sepsis survivals increase the risk of dementia or cognitive impairment remains to be further explored.

Objective

The objective of this study was to determine whether sepsis survivals increase the risk of dementia or cognitive impairment.

Methods

We searched PubMed, Cochrane Library, Web of Science, and EMBASE databases for cohort studies or case-control studies from their inception to November 5, 2021. The quality of this study was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). The Stata software (version 15.1) was used to calculate the odds ratio (OR) of dementia or cognitive impairment in sepsis survivals. Subgroup and sensitivity analyses were performed to assess the source of heterogeneity. Funnel plots and Egger’s test were used to detect the publication bias.

Results

Eight studies (i.e., seven cohort studies and one case-control study) involving 891,562 individuals were included. The quality assessment results showed that the average score of NOS was over 7, and the overall quality of the included studies was high. Pooled analyses indicated that sepsis survivals were associated with an increased risk of all-cause dementia (OR = 1.62, 95% CI = 1.23–2.15, I2 = 96.4%, p = 0.001). However, there was no obvious association between sepsis survivals and the risk of cognitive impairment (OR = 1.77, 95% CI = 0.59–5.32, I2 = 87.4%, p = 0.306). Subgroup analyses showed that severe sepsis was associated with an increased risk of dementia or cognitive impairment (OR = 1.99, 95% CI = 1.19–3.31, I2 = 75.3%, p = 0.008); such risk was higher than that of other unspecified types of sepsis (OR = 1.47, 95% CI = 1.04–2.09, I2 = 97.6%, p = 0.029).

Conclusion

Sepsis survivals are associated with an increased risk of all-cause dementia but not with cognitive impairment. Appropriate management and prevention are essential to preserve the cognitive function of sepsis survivors and reduce the risk of dementia.
Genoarchitecture of the Early Postmitotic Pretectum and the Role of Wnt Signaling in Shaping Pretectal Neurochemical Anatomy in Zebrafish
Authors: Brożko Nikola , Baggio Suelen , Lipiec Marcin A. , Jankowska Marta , Szewczyk Łukasz M. , Gabriel Michael O. , Chakraborty Chaitali , Ferran José L. , Wiśniewska Marta B.
Published: March 2022

The pretectum has a distinct nuclear arrangement and complex neurochemical anatomy. While previous genoarchitectural studies have described rostrocaudal and dorsoventral progenitor domains and subdomains in different species, the relationship between these early partitions and its later derivatives in the mature anatomy is less understood. The signals and transcription factors that control the establishment of pretectal anatomy are practically unknown. We investigated the possibility that some aspects of the development of pretectal divisions are controlled by Wnt signaling, focusing on the transitional stage between neurogenesis and histogenesis in zebrafish. Using several molecular markers and following the prosomeric model, we identified derivatives from each rostrocaudal pretectal progenitor domain and described the localization of gad1b-positive GABAergic and vglut2.2-positive glutamatergic cell clusters. We also attempted to relate these clusters to pretectal nuclei in the mature brain. Then, we examined the influence of Wnt signaling on the size of neurochemically distinctive pretectal areas, using a chemical inhibitor of the Wnt pathway and the CRISPR/Cas9 approach to knock out genes that encode the Wnt pathway mediators, Lef1 and Tcf7l2. The downregulation of the Wnt pathway led to a decrease in two GABAergic clusters and an expansion of a glutamatergic subregion in the maturing pretectum. This revealed an instructive role of the Wnt signal in the development of the pretectum during neurogenesis. The molecular anatomy presented here improves our understanding of pretectal development during early postmitotic stages and support the hypothesis that Wnt signaling is involved in shaping the neurochemical organization of the pretectum.
The Role of Paternal Involvement on Behavioral Sensitive Responses and Neurobiological Activations in Fathers: A Systematic Review
Authors: Giannotti Michele , Gemignani Micol , Rigo Paola , Venuti Paola , De Falco Simona
Published: March 2022

As fathering research has flourished, a growing body of studies has focused on behavioral and neurobiological mechanisms, respectively associated with caregiving sensitivity and responsiveness to infant stimuli. However, the association between these aspects and the key concept of paternal involvement in childcare (i.e., contribution in infant care in terms of time, availability, and responsibility) has been poorly investigated. The current work aims to systematically review the role of involvement in childcare on both neural activations and sensitive behaviors in fathers by examining (a) how paternal involvement has been measured and (b) whether paternal involvement has been associated with neurobiological activation and behavioral sensitive responses. Inclusion criteria were peer-reviewed quantitative studies, concerning fathers responding to infant stimuli at neurobiological or behavioral level, and including a quantitative measurement of paternal involvement in childcare. A quality rating for each study has been performed based on the measurements adopted to assess paternal involvement. Of 2,529 articles, 27 studies were included. According to our quality rating, 10 out of 27 studies included fairly good-standard measures for measuring paternal involvement, whereas 17 studies used good-standard measures. In addition, 11 studies provided details of paternal involvement in the context of neurobiological responses to infant stimuli, whereas 16 addressed paternal sensitive behaviors. Overall, only 8 studies reported relevant findings about the relationship between paternal involvement and neurobiological responses or sensitive behaviors in fathers. The present study is the first systematically evaluating the scope of paternal involvement in the field of Paternal Brain and fathers' sensitive responsiveness research. When high-standard measures are used, paternal involvement seems to play a significant role in modulating both the hormonal and the neural pathways associated with paternal behaviors. Remarkably, the role of paternal engagement may underpin an adaptive nurturance that is not dependent on pregnancy and childbirth but on caregiving experience. A promising positive link between paternal involvement and behavioral sensitivity may be expected in further studies, which will need to corroborate our conclusion by adopting detailed and appropriate measures assessing paternal involvement. As a future line of research, the inclusion of gay fathers may be beneficial for the field.
Craniopharyngioma and Metabolic Syndrome: A 5-Year Follow-Up Single-Center Experience
Authors: Scarano Elisabetta , Solari Domenico , Riccio Enrico , Arianna Rossana , Somma Teresa , Cavallo Luigi Maria , Romano Fiammetta , Colao Annamaria , Di Somma Carolina
Published: March 2022

Patients with craniopharyngioma often have comorbidities, such as obesity and hypopituitarism. These two conditions affect each other and worsen the quality of life of patients, which lead to a higher risk of morbidity and mortality. In addition, abdominal obesity, measured as waist circumference (WC), is together with other parameters [arterial hypertension, hyperglycemia, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol], one of the components of metabolic syndrome (MS). Each one of these morbidities occurs in patients with craniopharyngioma more frequently than in the remaining population. On these bases, we evaluated metabolic parameters in patients with craniopharyngioma at the time of diagnosis and after a 5-year follow-up, which compares these data with those of age-, gender-, WC-, and body mass index (BMI)-matched controls. In addition, we evaluated the prevalence of MS according to IDF criteria (MS-IDF) and the prevalence of MS according to ATP III (MS-ATPIII) criteria in patients and controls at baseline and after 5 years. We recruited 20 patients with craniopharyngioma (age 38.5 ± 15 years, 10 M) and 20 age-, gender-, WC- and BMI-matched controls (age 34.16 ± 13.19 years, 10 M). In all patients and controls, we evaluated the following: anthropometric features [height, weight, BMI, WC, hip circumference (HC) and waist-to-hip ratio (WHR)], systolic blood pressure (SBP) and diastolic blood pressure (DBP), lipid profile [total cholesterol (TC), HDL, low-density lipoprotein (LDL) cholesterol, triglycerides (TG)], and blood glucose at baseline and after 5 years. The prevalence of MS, according to IDF and ATPIII criteria, was calculated in the two groups at baseline and after 5 years. According to our results, at baseline, patients with craniopharyngioma had a worse metabolic profile than controls and a higher prevalence of MS. Besides, at a 5-year follow-up, patients still had impaired metabolic characteristics and more frequent MS (according to IDF and ATPIII criteria) when compared to controls. These data confirm that MS in patients with craniopharyngioma is unresponsive to life-changing interventions and to a common pharmacological approach. Other factors may be involved in the evolution of these conditions; so, further studies are needed to establish the correct management of these patients.
The Role of Motor Inhibition During Covert Speech Production
Authors: Nalborczyk Ladislas , Debarnot Ursula , Longcamp Marieke , Guillot Aymeric , Alario F-Xavier
Published: March 2022

Covert speech is accompanied by a subjective multisensory experience with auditory and kinaesthetic components. An influential hypothesis states that these sensory percepts result from a simulation of the corresponding motor action that relies on the same internal models recruited for the control of overt speech. This simulationist view raises the question of how it is possible to imagine speech without executing it. In this perspective, we discuss the possible role(s) played by motor inhibition during covert speech production. We suggest that considering covert speech as an inhibited form of overt speech maps naturally to the purported progressive internalization of overt speech during childhood. We further argue that the role of motor inhibition may differ widely across different forms of covert speech (e.g., condensed vs. expanded covert speech) and that considering this variety helps reconciling seemingly contradictory findings from the neuroimaging literature.
Preventing Sleep Disruption With Bright Light Therapy During Chemotherapy for Breast Cancer: A Phase II Randomized Controlled Trial
Authors: Rissling Michelle , Liu Lianqi , Youngstedt Shawn D. , Trofimenko Vera , Natarajan Loki , Neikrug Ariel B. , Jeste Neelum , Parker Barbara A. , Ancoli-Israel Sonia
Published: March 2022

Purpose

The goal of this study was to examine whether daily increased morning light exposure would maintain or improve sleep and the circadian pattern of relatively more activity in the day and less during the night in women undergoing chemotherapy for breast cancer.

Patients and Methods

Participants were 39 women with newly diagnosed breast cancer, randomized to either 30-mins of daily morning bright white light (BWL) or dim red light (DRL). Sleep/wake was measured objectively for 72-h with wrist actigraphy and subjectively with the Pittsburgh Sleep Quality Index (PSQI) prior to and during chemotherapy cycles 1 and 4. The study was registered with the National Institutes of Health ClinicalTrials.gov (Clinical Trials number: NCT00478257).

Results

Results from actigraphy suggested that compared to the DRL group, women in the BWL group had longer night-time sleep, fewer sleep disturbances during the night, and had fewer and shorter daytime naps at the end of cycle 4 of chemotherapy as well as exhibiting less activity at night and more activity during the day by the end of cycle 4. Results from PSQI indicated that components of sleep quality improved but daytime dysfunction deteriorated during cycle 4 treatment in the BWL group; meanwhile the DRL group used more sleep medications in the treatment weeks which might have led to the improved sleep quality during the recovery weeks of both cycles.

Conclusion

These results suggest that bright white light therapy administered every morning on awakening may protect women undergoing chemotherapy for breast cancer from nighttime sleep and daytime wake disruption. Randomized clinical trials in larger samples are needed to confirm these findings.
Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions
Authors: Fowler Sophie , Hoedt Emily C. , Talley Nicholas J. , Keely Simon , Burns Grace L.
Published: March 2022

Circadian rhythms are cyclic patterns of physiological, behavioural and molecular events that occur over a 24-h period. They are controlled by the suprachiasmatic nucleus (SCN), the brain’s master pacemaker which governs peripheral clocks and melatonin release. While circadian systems are endogenous, there are external factors that synchronise the SCN to the ambient environment including light/dark cycles, fasting/fed state, temperature and physical activity. Circadian rhythms also provide internal temporal organisation which ensures that any internal changes that take place are centrally coordinated. Melatonin synchronises peripheral clocks to the external time and circadian rhythms are regulated by gene expression to control physiological function. Synchronisation of the circadian system with the external environment is vital for the health and survival of an organism and as circadian rhythms play a pivotal role in regulating GI physiology, disruption may lead to gastrointestinal (GI) dysfunction. Disorders of gut-brain interactions (DGBIs), also known as functional gastrointestinal disorders (FGIDs), are a group of diseases where patients experience reoccurring gastrointestinal symptoms which cannot be explained by obvious structural abnormalities and include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Food timing impacts on the production of melatonin and given the correlation between food intake and symptom onset reported by patients with DGBIs, chronodisruption may be a feature of these conditions. Recent advances in immunology implicate circadian rhythms in the regulation of immune responses, and DGBI patients report fatigue and disordered sleep, suggesting circadian disruption. Further, melatonin treatment has been demonstrated to improve symptom burden in IBS patients, however, the mechanisms underlying this efficacy are unclear. Given the influence of circadian rhythms on gastrointestinal physiology and the immune system, modulation of these rhythms may be a potential therapeutic option for reducing symptom burden in these patients.
Characterisation of the Function of a SINE-VNTR-Alu Retrotransposon to Modulate Isoform Expression at the MAPT Locus
Authors: Fröhlich Alexander , Pfaff Abigail L. , Bubb Vivien J. , Koks Sulev , Quinn John P.
Published: March 2022

SINE-VNTR-Alu retrotransposons represent one class of transposable elements which contribute to the regulation and evolution of the primate genome and have the potential to be involved in genetic instability and disease progression. However, these polymorphic elements have not been extensively analysed when addressing the missing heritability of neurodegenerative diseases, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). SVA_67, a retrotransposon insertion polymorphism, is located in a 1.8 Mb region of high linkage disequilibrium, called the MAPT locus, which is known to contribute to increased risk of developing PD, frontotemporal dementia and other tauopathies. To investigate the role of SVA_67 in directing differential gene expression at this locus, we characterised the impact of SVA_67 allele dosage on isoform expression of several genes in the MAPT locus using the datasets from both the Parkinson’s Progression Markers Initiative and New York Genome Center Consortium Target ALS cohort. The Parkinson’s data was from gene expression in the blood and the ALS data from a variety of CNS regions and allowed us to demonstrate that SVA_67 presence or absence correlated with both isoform- and tissue-specific expression of multiple genes at this locus. This study highlights the importance of addressing SVA polymorphism in disease genetics to gain insight into a better understanding of the role of these regulatory domains to a variety of neurodegenerative diseases.
Association Between Dietary Protein Intake and Sleep Quality in Middle-Aged and Older Adults in Singapore
Authors: Sutanto Clarinda Nataria , Loh Wen Wei , Toh Darel Wee Kiat , Lee Delia Pei Shan , Kim Jung Eun
Published: March 2022

Poor sleep has been associated with the increased risk of developing detrimental health conditions. Diet and certain nutrients, such as dietary protein (PRO) may improve sleep. This cross-sectional study aimed to investigate the relationship between PRO intake, their amino acid components, and sources with sleep quality in middle-aged and older adults residing in Singapore. A dataset of 104 healthy subjects between the age of 50 and 75 years old were used. Collected data included 3-day food record and sleep quality [sleep duration, global sleep score (GSS), sleep latency (SL), and sleep efficiency (SE)]. The collected 3-day food records were extracted for PRO, tryptophan (Trp), and large neutral amino acid (LNAA) intake. PRO intake was further categorized into plant and animal PRO. A multivariate multiple linear regression (MLR) was performed to assess the association between PRO intake and sleep quality. Dietary Trp:LNAA ratio was positively associated with sleep duration (βtotal: 108.234 h; p: 0.005) after multiple covariates adjustment. Similarly, plant Trp (βplant: 2.653 h/g; p: 0.020) and plant Trp:LNAA (βplant: 54.006 h; p: 0.008) was positively associated with sleep duration. No significant associations were observed for both SL and SE. Sleep duration in middle-aged and older Singaporean adults was positively associated with dietary Trp and Trp:LNAA, especially when obtained from plant sources.
An Overview of Antimicrobial Activity of Lysozyme and Its Functionality in Cheese
Authors: Khorshidian Nasim , Khanniri Elham , Koushki Mohammad Reza , Sohrabvandi Sara , Yousefi Mojtaba
Published: March 2022

Due to the concern of consumers about the presence of synthetic preservatives, researchers and food manufacturers have recently conducted extensive research on the limited use of these preservatives and the introduction and use of natural preservatives, such as herbal extracts and essential oils, bacteriocins, and antimicrobial enzymes. Lysozyme is a natural enzyme with antimicrobial activity that has attracted considerable attention to be potentially utilized in various industries. Since lysozyme is an intrinsic component of the human immune system and has low toxicity; it could be considered as a natural antimicrobial agent for use in food and pharmaceutical industries. Lysozyme exerts antimicrobial activity against microorganisms, especially Gram-positive bacteria, by hydrolyzing 1,4-beta-linkages between N-acetylmuramic acid and N-acetylglucosamine in the cell wall. In addition, increased antimicrobial activity of lysozyme against Gram-negative bacteria could be achieved by the modification of lysozyme through physical or chemical interactions. Lysozyme is presented as a natural preservative in mammalian milk and can be utilized as a bio-preservative in dairy products, such as cheese. Both bacteria and fungi can contaminate and spoil the cheese; especially the one that is made traditionally by raw milk. Furthermore, uncontrolled and improper processes and post-pasteurization contamination can participate in the cheese contamination. Therefore, besides common preservative strategies applied in cheese production, lysozyme could be utilized alone or in combination with other preservative strategies to improve the safety of cheese. Hence, this study aimed to review the antimicrobial properties of lysozyme as natural antimicrobial enzyme and its functionality in cheese.
Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges
Authors: Kang Synat , Li Yisheng , Qiao Jingqiao , Meng Xiangyu , He Ziqian , Gao Xuefeng , Yu Li
Published: March 2022

The cytogenetic abnormalities and molecular mutations involved in acute myeloid leukemia (AML) lead to unique treatment challenges. Although adoptive T-cell therapies (ACT) such as chimeric antigen receptor (CAR) T-cell therapy have shown promising results in the treatment of leukemias, especially B-cell malignancies, the optimal target surface antigen has yet to be discovered for AML. Alternatively, T-cell receptor (TCR)-redirected T cells can target intracellular antigens presented by HLA molecules, allowing the exploration of a broader territory of new therapeutic targets. Immunotherapy using adoptive transfer of WT1 antigen-specific TCR-T cells, for example, has had positive clinical successes in patients with AML. Nevertheless, AML can escape from immune system elimination by producing immunosuppressive factors or releasing several cytokines. This review presents recent advances of antigen-specific TCR-T cells in treating AML and discusses their challenges and future directions in clinical applications.
Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity
Authors: Lee Wongeun , Kim Dong Kwon , Synn Chun-Bong , Lee Hee Kyu , Park Sungho , Jung Dong-Sik , Choi Yewon , Kim Jae Hwan , Byeon Youngseon , Kim Young Seob , Lee Seul , Lee Soyeon , Joo Yunjoo , Lee Eun Ji , Yun Mi Ran , Heo Seong Gu , Yang Wookyeom , Jung Ji Eun , Kim Eun Kyung , Park Jooyeon , Park June Dong , Lee Doo Jae , Kim Hyeon-Woo , Lim Sun Min , Hong Min Hee , Ahn Beung-Chul , Lee Jii Bum , Pyo Kyoung-Ho
Published: March 2022

A recently developed treatment strategy for lung cancer that combines immune checkpoint inhibitors with chemotherapy has been applied as a standard treatment for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and it has improved the outcomes of chemotherapy. Maintenance treatment with anti-PD-1 antibody (aPD-1) enhances the effect of immunochemical combination therapy and improves therapeutic efficacy, which contributes toward a significant improvement in patient survival rates. The AXL receptor tyrosine kinase (AXL), which is expressed in tumor cells, plays an essential role in the resistance of cancers to chemotherapy and immunotherapy, and stimulates signaling associated with epithelial-mesenchymal transition (EMT) in metastatic cancer. AXL is thus an attractive target for controlling resistance to anti-tumor therapies. In this study, we examined the effect of AXL inhibitors on immune activation and tumor growth in TC1 and C3PQ mouse tumor models, in the context of clinical immunotherapy/chemotherapy and maintenance treatment, using an aPD-1 with/without pemetrexed. To determine the optimal timing for administration of SKI-G-801, an AXL inhibitor, we investigated its anti-tumor effects based on inclusion at the immunochemotherapy and maintenance therapy stages. We also performed flow cytometry-based immune profiling of myeloid cells and lymphoid cells at different points in the treatment schedule, to investigate the immune activation and anti-tumor effects of the AXL inhibitor. The addition of SKI-G-801 to the immune checkpoint inhibitor and chemotherapy stage, as well as the maintenance therapy stage, produced the best anti-tumor results, and significant tumor growth inhibition was observed in both the TC1 and C3PQ models. Both models also exhibited increased proportion of effector memory helper T cells and increased expression of CD86+ macrophages. Especially, regulatory T cells were significantly reduced in the TC1 tumor model and there was an increase in central memory cytotoxic T cell infiltration and an increased proportion of macrophages with high CD80 expression in the C3PQ tumor model. These results suggest increased infiltration of T cells, consistent with previous studies using AXL inhibitors. It is expected that the results from this study will serve as a stepping stone for clinical research to improve the existing standard of care.