bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer
Authors: Clubb James H. A. , Kudling Tatiana V. , Heiniö Camilla , Basnet Saru , Pakola Santeri , Cervera Carrascón Víctor , Santos João Manuel , Quixabeira Dafne C. A. , Havunen Riikka , Sorsa Suvi , Zheng Vincent , Salo Tuula , Bäck Leif , Aro Katri , Tulokas Sanni , Loimu Venla , Hemminki Akseli
Published: March 2022

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNFα and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naïve and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNFα and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3+ tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45+ tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo, in both ICI naïve and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNFα and mIL-2 compared to monotherapies. This observation was verified by striking CD3+ TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNFα and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNFα and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1.
SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation
Authors: Perico Luca , Morigi Marina , Galbusera Miriam , Pezzotta Anna , Gastoldi Sara , Imberti Barbara , Perna Annalisa , Ruggenenti Piero , Donadelli Roberta , Benigni Ariela , Remuzzi Giuseppe
Published: March 2022

Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA. In vitro experiments were performed on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). The expression of adhesive molecules was studied by immunofluorescence and leukocyte adhesion and platelet aggregation were assessed under flow conditions. Angiotensin converting enzyme 2 (ACE2) and AMPK expression were investigated by Western Blot analysis. In addition, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist, or complement inhibitors. Our results show that significant levels of spike protein were found in the 30.4% of severe COVID-19 patients. In vitro, the activation of endothelial cells with S1 protein, via ACE2, impaired AMPK signalling, leading to robust leukocyte recruitment due to increased adhesive molecule expression and thrombomodulin loss. This S1-induced pro-inflammatory phenotype led to exuberant C3 and C5b-9 deposition on endothelial cells, along with C3a and C5a generation that further amplified S1-induced complement activation. Functional blockade of ACE2 or complement inhibition halted S1-induced platelet aggregates by limiting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. Overall, we demonstrate that SARS-CoV-2-derived S1 is sufficient in itself to propagate inflammatory and thrombogenic processes in the microvasculature, amplified by the complement system, recapitulating the thromboembolic complications of COVID-19.
Effect of Graphene Nanoplatelets on Tribological Properties of Bacterial Cellulose/Polyolester Oil Bio-Lubricant
Authors: Fuadi Zahrul , Rahmadiawan Dieter , Kurniawan Rudi , Mulana Farid , Abral Hairul , Nasruddin Nasruddin , Khalid Mohammad
Published: March 2022

The demand for bio-degradable lubricants is continuously increasing due to environmental concerns. One of the methods to achieve the bio-degradability property of lubricants is by using nanoparticles from bio-resources as additives in bio-degradable oils. Among the nanomaterials are nanofibers, cellulose, and graphene nanoplatelets. They can be mixed in Polyolester (POE) oil to produce lubricants for tribological applications. In a previous study, it has been confirmed that friction and wear of the tribo-pair reduced from 5 to 10% by mixing various volume percentages of bacterial cellulose (BC) into PEO as the base lubricant. The tribological performance BC containing POE base lubricant can further be enhanced by incorporating graphene nanoplatelets. This study shows that the specific wear rate of the material decreased by 20% by adding graphene nanoplatelets in BC containing POE oil. The friction and wear improvement can be related to the formation of tribofilm on the contact interface. EDS analysis indicates that oxygen played an important role in the friction and wear performance of the POE oil-based lubricant with BC and graphene additives. The tribofilm shows significant traces of oxygen elements. The presence of graphene nanoplatelets in POE oil removed the oxygen-rich layer but could not reduce the wear rate. However, incorporating both graphene and BC in POE oil significantly improved friction and wear, although the oxygen element was still traceable on the contact interface.
Transformation of Health and Social Care Systems—An Interdisciplinary Approach Toward a Foundational Architecture
Authors: Blobel Bernd , Oemig Frank , Ruotsalainen Pekka , Lopez Diego M.
Published: March 2022

Objective

For realizing pervasive and ubiquitous health and social care services in a safe and high quality as well as efficient and effective way, health and social care systems have to meet new organizational, methodological, and technological paradigms. The resulting ecosystems are highly complex, highly distributed, and highly dynamic, following inter-organizational and even international approaches. Even though based on international, but domain-specific models and standards, achieving interoperability between such systems integrating multiple domains managed by multiple disciplines and their individually skilled actors is cumbersome.

Methods

Using the abstract presentation of any system by the universal type theory as well as universal logics and combining the resulting Barendregt Cube with parameters and the engineering approach of cognitive theories, systems theory, and good modeling best practices, this study argues for a generic reference architecture model moderating between the different perspectives and disciplines involved provide on that system. To represent architectural elements consistently, an aligned system of ontologies is used.

Results

The system-oriented, architecture-centric, and ontology-based generic reference model allows for re-engineering the existing and emerging knowledge representations, models, and standards, also considering the real-world business processes and the related development process of supporting IT systems for the sake of comprehensive systems integration and interoperability. The solution enables the analysis, design, and implementation of dynamic, interoperable multi-domain systems without requesting continuous revision of existing specifications.
Two-Week Central Macular Thickness Reduction Rate >37% Predicts the Long-Term Efficacy of Anti-vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Retinal Vein Occlusion
Authors: Zhou Jialin , Ma Huafeng , Zhou Xiyuan , Wang Qiuyu , Li Weihou , Luo Shuai , Cai Chang , Li Zefeng , Liu Danning
Published: March 2022

Objective

To determine if the early response assessments can predict the long-term efficacy of anti-vascular endothelial growth factor (VEGF) treatment for macular edema secondary to retinal vein occlusion (RVO-ME).

Methods

A retrospective study of patients with diagnosis of RVO-ME and intravitreal anti-VEGF treatment was conducted. Clinical characteristics including age, gender, disease subtype and disease duration were recorded at baseline. The best corrected visual acuity (BCVA and logMAR), intraocular pressure (IOP), and central macular thickness (CMT) were recorded at baseline, 2 weeks, and every month (months 1–6) after injection. Further, we compared the early response assessments between the cured group (6-month CMT ≤ 250 μm) and the uncured group (6-month CMT > 250 μm).

Results

A total of 164 eyes in 164 patients (77 male and 87 female) were included. At each post-injection time point, both BCVA and CMT are significantly decreased from baseline (all P < 0.001). Spearman’s test showed that 2-week CMT reduction rate after the first injection was negatively correlated with BCVA at 6 months (r = −0.359, P < 0.001). Compared with the uncured group (47 cases), the cured group (117 cases) was younger (59.53 ± 11.68 vs. 65.19 ± 13.10 years old, P < 0.01), had more BRVO patients (76.1% vs. 44.7%, P < 0.01), a shorter disease duration (1.92 ± 2.43 vs. 5.05 ± 4.32 months, P < 0.01), lower baseline CMT (527.09 ± 154.95 vs. 768.96 ± 287.75 μm, P < 0.01), and lower baseline BCVA (0.86 ± 0.44 vs. 1.31 ± 0.51, P < 0.01). At each post-injection time point, the cured group had lower CMT and BCVA values when compared to the uncured group (all P < 0.01), and the 2-week CMT reduction rate was identified as the earliest response time to predict the long-term treatment efficacy. Moreover, ROC curve analysis indicated that a 2-week CMT reduction rate >37% yielded the best cut-off point for predicting the long-term cure of anti-VEGF treatment at 6 months (P < 0.001). Multivariable logistic regression confirmed that the 2-week CMT reduction rate >37% was independently associated with the 6-month cured rate (OR = 9.639, 95% Cl = 1.030–90.227, P = 0.047).

Conclusion

Age, disease duration, baseline CMT, and baseline BCVA are associated with visual outcomes at 6-month of anti-VEGF treatment for RVO-ME. The “2-week CMT reduction rate >37%” after the first injection is an independent factor to predict better long-term outcomes.
Mixed Effects of Soil Compaction on the Nitrogen Cycle Under Pea and Wheat
Authors: Longepierre Manon , Feola Conz Rafaela , Barthel Matti , Bru David , Philippot Laurent , Six Johan , Hartmann Martin
Published: March 2022

Soil compaction caused by highly mechanized agriculture can constrain soil microbial diversity and functioning. Physical pressure on the soil decreases macropores and thereby limits oxygen diffusion. The associated shift from aerobic to anaerobic conditions can reduce nitrification and promote denitrification processes, leading to nitrogen (N) losses and N depletion that affect plant productivity. High soil moisture content during trafficking can exacerbate the negative effects of soil compaction. However, the extent to which soil moisture amplifies the effects of compaction on the soil microbiome and its control over N cycling is not well understood. Using a controlled greenhouse experiment with two different crops (pea and wheat), we compared the effects of compaction at three different soil moisture levels on soil physicochemical properties, microbial diversity, and the abundance of specific N species and quantification of associated microbial functional groups in the N cycle. Soil compaction increased bulk density from 15% (light compaction) to 25% (severe compaction). Compaction delayed germination in both crops and reduced yield by up to 60% for pea and 40% for wheat. Compaction further induced crop-specific shifts in microbial community structures. After compaction, the relative abundance of denitrifiers increased along with increased nitrate (NO3–) consumption and elevated nitrous oxide (N2O) concentrations in the soil pores. Conversely, the relative abundance of nitrifiers remained stable under compaction, but potentially decelerated nitrification rates, resulting in ammonium (NH4+) accumulation in the soil. This study showed that soil compaction effects are proportional to the initial soil moisture content, which could serve as a good indicator of compaction severity on agricultural fields. However, the impact of soil compaction on crop performance and on microbial communities and functions associated with the N cycle were not necessarily aligned. These findings demonstrate that not only the soil physical properties but also various biological indicators need to be considered in order to provide more precise recommendations for developing sustainable farming systems.
Quorum Sensing Inhibition and Metabolic Intervention of 4-Hydroxycinnamic Acid Against Agrobacterium tumefaciens
Authors: Zhou Jin-Wei , Ji Peng-Cheng , Jiang Huan , Tan Xiao-Juan , Jia Ai-Qun
Published: March 2022

The natural product 4-hydroxycinnamic acid (HA) was firstly isolated from the metabolites of Phomopsis liquidambari, one endophytic fungus from Punica granatum leaves. The anti-QS potential of HA was evaluated by β-galactosidase assay and acylated homoserine lactones (AHL) analysis. The MIC of HA was > 1.20 mM. Exposure to HA at sub-MIC concentrations (0.30–0.60 mM) remarkably reduced the β-galactosidase activity and AHL secretion. Transcriptional analysis by qRT-PCR and docking simulation indicated that HA functions as an anti-QS agent by inhibiting the transcriptional levels of traI and traR rather than signal mimicry. The blocked QS lead to suppressed biofilm formation, motilities, and flagella formation after exposure to HA at concentrations ranging from 0.30 to 0.80 mM. The dysfunctional QS also resulted in repressed antioxidant enzymes and intensified oxidative stress. The intensified oxidative stress destroyed membrane integrity, induced energy supply deficiency, resulted in disorder of protein and nuclear acid metabolism, and ultimately weakened pathogenicity of A. tumefaciens. HA may have promising potential for controlling A. tumefaciens.
Dissemination Dynamics of HIV-1 Subtype B Pandemic and Non-pandemic Lineages Circulating in Amazonas, Brazil
Authors: Arantes Ighor , Gräf Tiago , Andrade Paula , Oliveira Chaves Yury , Guimarães Monick Lindenmeyer , Bello Gonzalo
Published: March 2022

The HIV-1 epidemic in the Amazonas state, as in most of Brazil, is dominated by subtype B. The state, nonetheless, is singular for its significant co-circulation of the variants BCAR, which can mostly be found in the Caribbean region, and BPAN, a clade that emerged in the United States and aggregates almost the totality of subtype B infections world-wide. The Amazonian HIV-1 epidemic provides a unique scenario to compare the epidemic potential of BPAN and BCAR clades spreading in the same population. To reconstruct the spatiotemporal dynamic and demographic history of both subtype B lineages circulating in Amazonas, we analyzed 1,272 HIV-1 pol sequences sampled in that state between 2009 and 2018. Our phylogeographic analyses revealed that while most BCAR infections resulted from a single successful founder event that took place in the Amazonas state around the late 1970s, most BPAN infections resulted from the expansion of multiple clusters seeded in the state since the late 1980s. Our data support the existence of at least four large clusters of the pandemic form in Amazonas, two of them nested in Brazil’s largest known subtype B cluster (BBR–I), and two others resulting from new introductions detected here. The reconstruction of the demographic history of the most prevalent BPAN (n = 4) and BCAR (n = 1) clades identified in Amazonas revealed that all clades displayed a continuous expansion [effective reproductive number (Re) > 1] until most recent times. During the period of co-circulation from the late 1990s onward, the Re of Amazonian BPAN and BCAR clusters behaved quite alike, fluctuating between 2.0 and 3.0. These findings support that the BCAR and BPAN variants circulating in the Brazilian state of Amazonas displayed different evolutionary histories, but similar epidemic trajectories and transmissibility over the last two decades, which is consistent with the notion that both subtype B variants display comparable epidemic potential. Our findings also revealed that despite significant advances in the treatment of HIV infections in the Amazonas state, BCAR and BPAN variants continue to expand and show no signs of the epidemic stabilization observed in other parts of the country.
Inhibition of Human Cytomegalovirus Particle Maturation by Activation of Liver X Receptor
Authors: Liu Bingnan , Ma Yanping , Huang Yujing , Liu Zhongyang , Ruan Qiang , Qi Ying
Published: March 2022

Human cytomegalovirus (HCMV), a herpesvirus family member, is a large, complex enveloped virus. The activation of liver X receptor (LXR) can significantly inhibit the replication of HCMV and weaken the virulence of progeny virus (unpublished data). Our results showed activated LXR affected some important viral protein expression and reduced cholesterol content in HCMV infected cells and virus particles. To further clarify the influence of activated LXR on HCMV replication, HCMV assembly and maturation processes were studied by transmission electron microscopy (TEM) in HCMV infected foreskin fibroblasts treated with LXR agonist GW3965. Results showed that activated LXR could reduce the envelope integrity of maturating virions. The functional stage of activated LXR on viral envelope integrity was mainly at virus assembly compartment (VAC) mediated envelopment but not structurally complete virus nucleocapsid formation and the egress of nucleocapsid from the nucleus to the cytoplasm mediated by nuclear egress complex. Reduced cholesterol synthesis and viral protein expression might interfere with the VAC-mediated envelopment. The nucleocapsid and tegument proteins enter the VAC area for the secondary envelope, which was interfered with and resulted in the defective particle, thereby affecting the amount and infectivity of the mature virus. The results indicate that inhibition of HCMV maturation is one mechanism of activated LXR inhibiting virus replication in infected cells.
Insights From the Lactobacillus johnsonii Genome Suggest the Production of Metabolites With Antibiofilm Activity Against the Pathobiont Candida albicans
Authors: Vazquez-Munoz Roberto , Thompson Angela , Russell Jordan T. , Sobue Takanori , Zhou Yanjiao , Dongari-Bagtzoglou Anna
Published: March 2022

Lactobacillus johnsonii is a probiotic bacterial species with broad antimicrobial properties; however, its antimicrobial activities against the pathobiont Candida albicans are underexplored. The aim of this study was to study the interactions of L. johnsonii with C. albicans and explore mechanisms of bacterial anti-fungal activities based on bacterial genomic characterization coupled with experimental data. We isolated an L. johnsonii strain (MT4) from the oral cavity of mice and characterized its effect on C. albicans growth in the planktonic and biofilm states. We also identified key genetic and phenotypic traits that may be associated with a growth inhibitory activity exhibited against C. albicans. We found that L. johnsonii MT4 displays pH-dependent and pH-independent antagonistic interactions against C. albicans, resulting in inhibition of C. albicans planktonic growth and biofilm formation. This antagonism is influenced by nutrient availability and the production of soluble metabolites with anticandidal activity.
Body Mass Index, Waist Circumference, and Cognitive Decline Among Chinese Older Adults: A Nationwide Retrospective Cohort Study
Authors: Liang Fang , Fu Jialin , Moore Justin B. , Zhang Xinge , Xu Yijia , Qiu Nan , Wang Yechuang , Li Rui
Published: March 2022

Background

The reported associations between body mass index (BMI), waist circumference (WC), and cognitive decline are not consistent, especially in older adults.

Objective

This study aims to investigate the longitudinal associations of BMI, WC, and their change values with cognitive decline among Chinese adults aged 60 years and older and to examine the potential moderating effect of sex on these relationships.

Methods

The participants in this study were from waves one to four (2011–2018) of the China Health and Retirement Longitudinal Study (CHARLS). Cognition function, BMI, and WC were measured at four examinations over 7 years. The interview-based cognitive assessments of memory, orientation and attention, and visuospatial ability were recorded. Standardized global cognitive scores were generated. BMI and WC were objectively measured. Mixed-effects models were performed to evaluate the associations.

Results

A final sample of 3,035 Chinese older adults [mean (SD) age, 66.94 (5.43) years; 40.16% (n = 1,219) women] were included. Higher BMI (estimate = 0.0107; SE = 0.0024; p < 0.0001) and WC (estimate = 0.0019; SE = 0.0006; p = 0.0037) were associated with slower cognition score decline over a 7-year follow-up, while greater BMI variability (estimate = −0.0365; SE = 0.0116; p = 0.0017) was related to faster cognition score decline. The results were not modified by sex. BMI-defined overweight (estimate = 0.0094; SE = 0.0043; p = 0.0298) was associated with a slower cognition score decline, and both large weight gain (estimate = −0.0266; SE = 0.0074; p = 0.0003) and large WC loss (estimate = −0.0668; SE = 0.0329; p = 0.0426) were associated with faster cognition score decline.

Conclusion

Among Chinese older adults, higher BMI, higher WC, and overweight are related to slower cognitive decline, while greater BMI variability, large weight gain, and large WC loss are associated with faster cognitive decline.
In Search for the Avian Trigeminal Magnetic Sensor: Distribution of Peripheral and Central Terminals of Ophthalmic Sensory Neurons in the Night-Migratory Eurasian Blackcap (Sylvia atricapilla)
Authors: Haase Katrin , Musielak Isabelle , Warmuth-Moles Leonie , Leberecht Bo , Zolotareva Anna , Mouritsen Henrik , Heyers Dominik
Published: March 2022

In night-migratory songbirds, neurobiological and behavioral evidence suggest the existence of a magnetic sense associated with the ophthalmic branch of the trigeminal nerve (V1), possibly providing magnetic positional information. Curiously, neither the unequivocal existence, structural nature, nor the exact location of any sensory structure has been revealed to date. Here, we used neuronal tract tracing to map both the innervation fields in the upper beak and the detailed trigeminal brainstem terminations of the medial and lateral V1 subbranches in the night-migratory Eurasian Blackcap (Sylvia atricapilla). The medial V1 subbranch takes its course along the ventral part of the upper beak to innervate subepidermal layers and the mucosa of the nasal cavity, whereas the lateral V1 subbranch runs along dorsolateral levels until the nostrils to innervate mainly the skin of the upper beak. In the trigeminal brainstem, medial V1 terminals innervate both the dorsal part and the ventral, magnetically activated part of the principal sensory trigeminal brainstem nuclei (PrV). In contrast, the lateral V1 subbranch innervates only a small part of the ventral PrV. The spinal sensory trigeminal brainstem nuclei (SpV) receive topographically ordered projections. The medial V1 subbranch mainly innervates rostral and medial parts of SpV, whereas the lateral V1 subbranch mainly innervates the lateral and caudal parts of SpV. The present findings could provide valuable information for further analysis of the trigeminal magnetic sense of birds.
The Duration of Stress Determines Sex Specificities in the Vulnerability to Depression and in the Morphologic Remodeling of Neurons and Microglia
Authors: Gaspar Rita , Soares-Cunha Carina , Domingues Ana Verónica , Coimbra Bárbara , Baptista Filipa I. , Pinto Luísa , Ambrósio António F. , Rodrigues Ana João , Gomes Catarina A.
Published: March 2022

Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and behavioral responses to chronic stress and also contribute to the development of stress-related psychopathologies. However, little is known about the impact of the duration of stress exposure upon microglia and neurons morphology, particularly considering sex differences. This issue deserves particular investigation, considering that the process of morphologic remodeling of neurons and microglia is usually accompanied by functional changes with behavioral expression. Here, we examine the effects of short and long unpredictable chronic mild stress (uCMS) protocols on behavior, evaluating in parallel microglia and neurons morphology in the dorsal hippocampus (dHIP) and in the nucleus accumbens (NAc), two brain regions involved in the etiology of depression. We report that long-term uCMS induced more behavioral alterations in males, which present anxiety and depression-like phenotypes (anhedonia and helplessness behavior), while females only display anxiety-like behavior. After short-term uCMS, both sexes presented anxiety-like behavior. Microglia cells undergo a process of morphologic adaptation to short-term uCMS, dependent on sex, in the NAc: we observed a hypertrophy in males and an atrophy in females, transient effects that do not persist after long-term uCMS. In the dHIP, the morphologic adaptation of microglia is only observed in females (hypertrophy) and after the protocol of long uCMS. Interestingly, males are more vulnerable to neuronal morphological alterations in a region-specific manner: dendritic atrophy in granule neurons of the dHIP and hypertrophy in the medium spiny neurons of the NAc, both after short- or long-term uCMS. The morphology of neurons in these brain regions were not affected in females. These findings raise the possibility that, by differentially affecting neurons and microglia in dHIP and NAc, chronic stress may contribute for differences in the clinical presentation of stress-related disorders under the control of sex-specific mechanisms.
Electrocorticography to Investigate Age-Related Brain Lateralization on Pediatric Motor Inhibition
Authors: Kuo Chao-Hung , Casimo Kaitlyn , Wu Jing , Collins Kelly , Rice Patrick , Chen Bo-Wei , Yang Shih-Hung , Lo Yu-Chun , Novotny Edward J. , Weaver Kurt E. , Chen You-Yin , Ojemann Jeffrey G.
Published: March 2022

Response inhibition refers to the ability to suppress inappropriate actions that interfere with goal-driven behavior. The inferior frontal gyrus (IFG) is known to be associated with inhibition of a motor response by assuming executive control over motor cortex outputs. This study aimed to evaluate the pediatric development of response inhibition through subdural electrocorticography (ECoG) recording. Subdural ECoG recorded neural activities simultaneously during a Go/No-Go task, which was optimized for children. Different frequency power [theta: 4–8 Hz; beta: 12–40 Hz; high-gamma (HG): 70–200 Hz] was estimated within the IFG and motor cortex. Age-related analysis was computed by each bandpass power ratio between Go and No-Go conditions, and phase-amplitude coupling (PAC) over IFG by using the modulating index metric in two conditions. For all the eight pediatric patients, HG power was more activated in No-Go trials than in Go trials, in either right- or left-side IFG when available. In the IFG region, the power over theta and HG in No-Go conditions was higher than those in Go conditions, with significance over the right side (p < 0.05). The age-related lateralization from both sides to the right side was observed from the ratio of HG power and PAC value between the No-Go and Go trials. In the pediatric population, the role of motor inhibition was observed in both IFG, with age-related lateralization to the right side, which was proved in the previous functional magnetic resonance imaging studies. In this study, the evidence correlation of age and response inhibition was observed directly by the evidence of cortical recordings.
Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production
Authors: Bjork Reed T. , Mortimore Nicholas P. , Loganathan Suvithanandhini , Zarnescu Daniela C.
Published: March 2022

Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as essential for a neuron’s ability to navigate developmental cues, and to establish, strengthen and remove synaptic connections throughout lifespan. Substantiating the role of RNA processing in the nervous system, several RNA binding proteins have been implicated in both developmental and age dependent neurodegenerative disorders. Of these, TDP-43 is an RNA binding protein that has emerged as a common denominator in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related disorders due to the identification of causative mutations altering its function and its accumulation in cytoplasmic aggregates observed in a significant fraction of ALS/FTD cases, regardless of etiology. TDP-43 is involved in multiple aspects of RNA processing including splicing, transport and translation. Given that one of the early events in disease pathogenesis is mislocalization from the nucleus to the cytoplasm, several studies have focused on elucidating the pathogenic role of TDP-43 in cytoplasmic translation. Here we review recent findings describing TDP-43 translational targets and potential mechanisms of translation dysregulation in TDP-43 proteinopathies across multiple experimental models including cultured cells, flies, mice and patient derived neurons.
Nanocomposite Coatings Based on Polyvinyl Alcohol and Montmorillonite for High-Barrier Food Packaging
Authors: Schiessl Stefan , Kucukpinar Esra , Cros Stéphane , Miesbauer Oliver , Langowski Horst-Christian , Eisner Peter
Published: March 2022

Materials with high barrier properties against oxygen are required for the packaging of many sensitive foods. Since commodity polymers lack these properties, additional barrier materials are used in plastic-based barrier packaging. These are usually more expensive than commodity polymers and, in higher fractions, also make recycling more difficult. Current developments, therefore, aim at barrier layers that are as thin as possible but retain the barrier properties. One approach is to incorporate nanoparticles into these layers. In this study, the barrier properties of nanocomposite coatings, consisting of unmodified polyvinyl alcohol (PVA), and dispersed stick-shaped halloysite (Hal) or platelet-shaped montmorillonite (MMT) silicate nanoparticles, were investigated. The PVA was dissolved in aqueous nanoparticle dispersions, which were prepared by mechanical shearing, to produce the so-called “nanolacquer.” Nanolacquers with nanoparticle concentrations of 7, 30, and 47 vol% with respect to PVA were applied in a single process step with k-bar on a polypropylene substrate film. The integration of 30 vol% platelet-shaped MMT enhances the barrier performance in comparison to pure PVA by a factor of 12 and 17 for oxygen and helium, respectively. Scanning electron microscopy (SEM) shows a homogeneous distribution and a parallel alignment of the nanoparticles within the coated layer. An increase in the crystallinity of PVA was observed due to the nanoparticle integration as demonstrated by x-ray diffraction (XRD) measurements. The investigation by Fourier transform infrared (FTIR) spectroscopy and the activation energy of the permeation coefficient indicate an interaction between the nanoparticles and the PVA. The theoretically calculated values for barrier enhancement accord well with the experimental values, which emphasizes that the gas barrier improvement for oxygen and helium is mainly dominated by the tortuous path effect.
PalatinoseTM (Isomaltulose) and Prebiotic Inulin-Type Fructans Have Beneficial Effects on Glycemic Response and Gut Microbiota Composition in Healthy Volunteers—A Real-Life, Retrospective Study of a Cohort That Participated in a Digital Nutrition Program
Authors: Kordowski Anna , Künstner Axel , Schweitzer Lisa , Theis Stephan , Schröder Torsten , Busch Hauke , Sina Christian , Smollich Martin
Published: March 2022

It is well-appreciated that the diet is a crucial tool to counteract cardiometabolic disturbances due to its impact on blood glucose concentration and gut microbiome. This retrospective analysis aimed to examine whether the inclusion of isomaltulose and prebiotic inulin-type fructans (ITF) into the habitual diet has an impact on glycemic control and gut microbiota. Furthermore, we examined interindividual differences in glycemic response to sugar replacement with isomaltulose. We retrospectively analyzed data of 117 individuals who participated in a digital nutrition program including a 14-day continuous glucose measurement. Participants underwent six test days with sweetened drinks (isomaltulose vs. sucrose) consumed with their usual breakfasts and lunches. Dinner was supplemented with ITF for 11 days. Postprandial glycemia and 24 h-glycemic variability were determined following test meals and days, respectively. Fecal microbiota was analyzed by 16S rRNA sequencing before and after test phase. Meals with isomaltulose-sweetened drinks compared to meals with sucrose-sweetened drinks induced lower postprandial glycemia. Moreover, glucose oscillations over 24 h were lower on isomaltulose when compared to sucrose test days and improved further during ITF supplementation. Furthermore, ITF modulated gut microbiota composition beneficially. Responder analysis revealed that 72% of participants benefited from the sugar replacement with isomaltulose and that their gut microbiota differed from the low responders. Taken together, the incorporation of isomaltulose and ITF into the habitual diet was shown to be an effective strategy to improve glucose control and beneficially modulate gut microbiota, and thereby aid to maintain metabolic health. Data indicate interindividual differences in glycemic response to ingredients and suggest that gut microbiota might be somehow related to it.
Hyperprogressive Disease After Immunotherapy: A Case Report of Pulmonary Enteric Adenocarcinoma
Authors: Hu Chun-Hong , Shi Shenghao , Dong Wen , Xiao Lizhi , Zang Hongjing , Wu Fang
Published: March 2022

Primary pulmonary enteric adenocarcinoma (PEAC) is a rare invasive adenocarcinoma clinically similar to metastatic colorectal adenocarcinoma (MCRC). Although many studies have addressed the differential diagnosis of PEAC, few have described the treatment of PEAC, especially using immunotherapy. This report describes a 61-year-old man who presented initially with pain in the ribs. Pathological analysis of biopsy samples shows malignant tumors of the right pleura, and next-generation sequencing of 26 genes showed a KRAS gene mutation. Positron emission tomography-computed tomography (PET-CT) found no evidence of gastrointestinal malignancy. Due to multiple metastases, the patient could not undergo radical surgery. The patient was treated with a combination chemotherapy regimen of paclitaxel plus carboplatin, along with sindilizumab immunotherapy, but, after one cycle of treatment, the tumor showed a hyperprogressive state. The patient is still being monitored regularly. These findings indicate that chemotherapy combined with immunotherapy may be ineffective in the treatment of primary PEAC with positive driver genes.
Comparative Effectiveness of Abiraterone and Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer in Taiwan
Authors: Li Pei-Yu , Lu Ying-Hao , Chen Chung-Yu
Published: March 2022

Background

Abiraterone and enzalutamide are widely used as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC); however, their efficacy in mCRPC has been inconsistently demonstrated in other outcome studies from real-world databases. The aim of our study was to assess the comparative effectiveness of abiraterone and enzalutamide in patients with mCRPC using real-world data from Taiwan.

Methods

This retrospective cohort population-based study included patients identified in the Taiwan National Health Insurance Research Database who had been diagnosed with mCRPC and who had taken abiraterone or enzalutamide between December 2014 and August 2017. The study’s outcome evaluated the differences in overall survival (OS) and time to treatment failure (TTF) between abiraterone and enzalutamide over a 15-month follow-up period. The patients were followed from the index date to when the outcome occurred, to December 31, 2018, or to the patients’ withdrawal from the National Health Insurance program. The estimated relative treatment effects of abiraterone and enzalutamide on OS and TTF were adjusted by the inverse probability of treatment weighting (IPTW) using the Kaplan–Meier method and a Cox proportional hazards model.

Results

The abiraterone and enzalutamide groups consisted of 1,046 and 118 patients, respectively. After IPTW adjustment, 1,164 patients in the abiraterone group and 1,158 in the enzalutamide group underwent an outcome evaluation. Enzalutamide showed a similar OS rate to that of abiraterone (57.58% vs. 49.51%, p = 0.095 by log-rank test). Enzalutamide significantly reduced the risk of death for mCRPC when compared with abiraterone [adjusted hazard ratio (aHR), 0.828; 95% CI 0.731–0.938]. However, similar results were not observed in the TTF outcomes (63.84% vs. 67.79%, p = 0.2651 by log-rank test; aHR, 0.902; 95% CI 0.812–1.002).

Conclusion

In conclusion, enzalutamide was associated with better OS for mCRPC than abiraterone in the Taiwan population. Our study showed that there was no statistically significant difference in TTF between enzalutamide and abiraterone. Studies with longer surveillance of enzalutamide and abiraterone using real-world databases are needed.
Intracranial Metastatic Disease: Present Challenges, Future Opportunities
Authors: Li Alyssa Y. , Gaebe Karolina , Jerzak Katarzyna J. , Cheema Parneet K. , Sahgal Arjun , Das Sunit
Published: March 2022

Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation.
Virtual Reality in the Management of Chronic Low Back Pain: A Scoping Review
Authors: Nagpal Ameet S. , Raghunandan Aditya , Tata Faye , Kibler Daniel , McGeary Donald
Published: March 2022

Virtual reality (VR) is a burgeoning treatment option for chronic pain. Its use has been heterogenous in the literature. This scoping review assesses the current literature for the use of VR in the treatment of chronic low back pain (CLBP). The following themes were identified by the analysis: safety and feasibility of VR, quality of life associated with VR treatment for CLBP, efficacy of VR to treat CLBP, and efficacy of VR to treat functional changes associated with CLBP. Gaps were identified after analysis of the extant literature. Although the nascent research uncovered in this scoping review found good evidence for safety and tolerability of VR, more studies of safety, acceptance, and satisfaction are recommended including focused studies of spinal pain risks specific to use of VR. Overall, the methodological quality of studies reviewed in this scoping review was poor and outcomes were limited to short-term posttreatment outcomes.
Etiologic Classification of 541 Infantile Spasms Cases: A Cohort Study
Authors: Peng Pan , Kessi Miriam , Mao Leilei , He Fang , Zhang Ciliu , Chen Chen , Pang Nan , Yin Fei , Pan Zou , Peng Jing
Published: March 2022

Objective

To explore the etiology of infantile spasms (IS) in a large Chinese cohort based on the United States National Infantile Spasms Consortium (NISC) classification.

Methods

In the present study, we recruited IS patients diagnosed at a single center (Xiangya Hospital, Central South University) between Jan 2010 and Aug 2019. Thereafter, we collected their clinical and genetic information retrospectively. Their underlying etiologies were classified according to the NISC classification and then compared in different scenarios to understand their distribution.

Results

A total of 541 patients with IS from 18 provinces were included in this study. The underlying etiology was identified in 53.2% of the cases: structural-acquired, 25.3%; genetic, 12.9%; genetic-structural, 7.2%; structural-congenital, 5.0%; metabolic, 2.4%; infections, 0.4% and immune, 0%. Whole-exome sequencing (WES) provided the highest diagnostic yield (26.9%). In structural-acquired IS, the proportion of hypoglycemic brain injuries was significant, second only to hypoxic-ischemic encephalopathy. There was no patient discovered to have Down syndrome. STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1 were the most frequently implicated genes. Genetic causes were found to be the most common cause of IS in the early onset group, while structural-acquired etiologies were common in males and preterm babies. Patients with pre-spasm seizures were associated with a higher proportion of identified causes than those without. Non-acquired structural etiologies were more common in patients without hypsarrhythmia than in those with hypsarrhythmia.

Significance

The most prevalent cause of IS was structural acquired followed by genetic causes. When brain MRI fails to detect the etiology, we propose WES as the next step. Structural-acquired IS and cases with genetic disorders are characteristic of the Chinese cohort, however, the etiology differs with the patient's age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia.
Tidal Breathing Pulmonary Function of Children With Allergic Rhinitis
Authors: Du Hui , Liu Xueru , Peng Fang , Chen Hebin , Wang Yanli
Published: March 2022

In order to investigate the characteristics of tidal breathing pulmonary function in children with allergic rhinitis, and explore its role in the relationship between allergic rhinitis and asthma, we conducted this prospective study from January 4, 2016 to January 30, 2019 in Wuhan children’s hospital. In this study, 49 children with simple allergic rhinitis were enrolled in the AR group; 50 children with allergic rhinitis concomitant with asthma were enrolled in the AR&A group; 43 healthy children were recruited in the control group. For individuals in each group, the assessment of tidal breath pulmonary function was performed after enrollment. Then participants in the AR group and control group were followed up for 1 year to observe their frequency of wheezing attacks. The parameters of tI/tE, tPTEF/tE, and VPTEF/VE of AR group were significantly higher than AR&A group (P < 0.001). The reduced proportion of tPTEF/tE and VPTEF/VE. in AR group were higher than that in control group (30.61% vs. 11.63%, P < 0.001; 24.49% vs. 11.63%, P < 0.001, respectively). The proportion of patients with reduced tPTEF/tE and VPTEF/VE who occurred recurrent wheezing was higher than that of patients with normal pulmonary function in AR group(P = 0.008). In conclusion, some children with allergic rhinitis has impaired tidal breathing pulmonary function. Tidal breathing pulmonary function test plays an important role in the diagnosis and assessment of children’s airway allergic diseases (AR and asthma).
Uncovering the Pharmacological Mechanisms of Gexia-Zhuyu Formula (GXZY) in Treating Liver Cirrhosis by an Integrative Pharmacology Strategy
Authors: Cao Xu , Liang Yijun , Liu Ruijia , Zao Xiaobin , Zhang Jiaying , Chen Guang , Liu Ruijie , Chen Hening , He Yannan , Zhang Jiaxin , Ye Yong’an
Published: March 2022

Liver cirrhosis (LC) is a fibrotic lesion of liver tissue caused by the repeated progression of chronic hepatitis. The traditional Chinese medicine Gexia-Zhuyu formula (GXZY) has a therapeutic effect on LC. However, its pharmacological mechanisms on LC remain elucidated. Here, we used the network pharmacology approach to explore the action mechanisms of GXZY on LC. The compounds of GXZY were from the traditional Chinese medicine systems pharmacology (TCMSP) database, and their potential targets were from SwissTargetPrediction and STITCH databases. The disease targets of LC came from GeneCards, DisGeNET, NCBI gene, and OMIM databases. Then we constructed the protein-protein interaction (PPI) network to obtain the key target genes. And the gene ontology (GO), pathway enrichment, and expression analysis of the key genes were also performed. Subsequently, the potential action mechanisms of GXZY on LC predicted by the network pharmacology analyses were experimentally validated in LC rats and LX2 cells. A total of 150 components in GXZY were obtained, among which 111 were chosen as key compounds. The PPI network included 525 targets, and the key targets were obtained by network topological parameters analysis, whereas the predicted key genes of GXZY on LC were AR, JUN, MYC, CASP3, MMP9, GAPDH, and RELA. Furthermore, these key genes were related to pathways in cancer, hepatitis B, TNF signaling pathway, and MAPK signaling pathway. The in vitro and in vivo experiments validated that GXZY inhibited the process of LC mainly via the regulation of cells proliferation and migration through reducing the expression of MMP9. In conclusion, through the combination of network pharmacology and experimental verification, this study offered more insight molecular mechanisms of GXZY on LC.