bluuebunny/crossref_metadata_2025 huggingface dataset:
Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19
Authors: Ali Youssif M. , Lynch Nicholas J. , Khatri Priyanka , Bamigbola Ifeoluwa E. , Chan Andrew C. Y. , Yabuki Munehisa , Demopulos Gregory A. , Heeney Jonathan L. , Pai Sumita , Baxendale Helen , Schwaeble Wilhelm J.
Published: April 2022

A high incidence of secondary Klebsiella pneumoniae and Staphylococcus aureus infection were observed in patients with severe COVID-19. The cause of this predisposition to infection is unclear. Our data demonstrate consumption of complement in acute COVID-19 patients reflected by low levels of C3, C4, and loss of haemolytic activity. Given that the elimination of Gram-negative bacteria depends in part on complement-mediated lysis, we hypothesised that secondary hypocomplementaemia is rendering the antibody-dependent classical pathway activation inactive and compromises serum bactericidal activity (SBA). 217 patients with severe COVID-19 were studied. 142 patients suffered secondary bacterial infections. Klebsiella species were the most common Gram-negative organism, found in 58 patients, while S. aureus was the dominant Gram-positive organism found in 22 patients. Hypocomplementaemia was observed in patients with acute severe COVID-19 but not in convalescent survivors three months after discharge. Sera from patients with acute COVID-19 were unable to opsonise either K. pneumoniae or S. aureus and had impaired complement-mediated killing of Klebsiella. We conclude that hyperactivation of complement during acute COVID-19 leads to secondary hypocomplementaemia and predisposes to opportunistic infections.
Glomerular Expression of S100A8 in Lupus Nephritis: An Integrated Bioinformatics Analysis
Authors: Qijiao Wei , Zhihan Chen , Makota Panashe , Qing Yan , Fei Gao , Zhihong Wang , He Lin
Published: April 2022

Introduction

Lupus nephritis (LN) is a major risk factor of morbidity and mortality. Glomerular injury is associated with different pathogeneses and clinical presentations in LN patients. However, the molecular mechanisms involved are not well understood. This study aimed to explore the molecular characteristics and mechanisms of this disease using bioinformatics analysis.

Methods

To characterize glomeruli in LN, microarray datasets GSE113342 and GSE32591 were downloaded from the Gene Expression Omnibus database and analyzed to determine the differentially expressed genes (DEGs) between LN glomeruli and normal glomeruli. Functional enrichment analyses and protein–protein interaction network analyses were then performed. Module analysis was performed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape software. Immunofluorescence staining was performed to identify the glomerular expression of S100A8 in various International Society of Nephrology/Renal Pathology Society (ISN/RPS) class LN patients. The image of each glomerulus was acquired using a digital imaging system, and the green fluorescence intensity was quantified using Image-Pro Plus software.

Results

A total of 13 DEGs, consisting of 12 downregulated genes and one upregulated gene (S100A8), were identified in the microarray datasets. The functions and pathways associated with the DEGs mainly include inflammatory response, innate immune response, neutrophil chemotaxis, leukocyte migration, cell adhesion, cell–cell signaling, and infection. We also found that monocytes and activated natural killer cells were upregulated in both GSE113342 and GSE32591. Glomerular S100A8 staining was significantly enhanced compared to that in the controls, especially in class IV.

Conclusions

The DEGs identified in the present study help us understand the underlying molecular mechanisms of LN. Our results show that glomerular S100A8 expression varies in different pathological types; however, further research is required to confirm the role of S100A8 in LN.
Comparison of the Toponomes of Alveolar Macrophages From Wild Type and Surfactant Protein A Knockout Mice and Their Response to Infection
Authors: Phelps David S. , Chinchilli Vernon M. , Zhang Xuesheng , Shearer Debra , Weisz Judith , Floros Joanna
Published: April 2022

Background

Surfactant protein-A (SP-A) plays a critical role in lung innate immunity by regulating alveolar macrophages (AM), expression of inflammatory mediators, and other host defense proteins. The toponome imaging system (TIS), a serial immunostainer, was used to study the AM toponome because it characterizes the localization of multiple markers and identifies marker combinations in each pixel as combinatorial molecular phenotypes (CMPs). We used TIS to study the AM toponome from wild type (WT) and SP-A knockout (KO) mice and changes following Klebsiella pneumoniae exposure.

Methods

WT or KO mice received intratracheal K. pneumoniae or vehicle and AM were obtained by bronchoalveolar lavage after one hour. AM were attached to slides and underwent TIS analysis. Images were analyzed to characterize all pixels. AM CMPs from WT vehicle (n=3) and infected (n=3) mice were compared to each other and to AM from KO (n=3 vehicle; n=3 infected). Histograms provided us with a tool to summarize the representation of each marker in a set of CMPs.

Results

Using the histograms and other tools we identified markers of interest and observed that: 1) Both comparisons had conserved (present in all group members) CMPs, only in vehicle AM and only in infected AM, or common to both vehicle and infected AM, (i.e., unaffected by the condition). 2) the CMP number decreased with infection in WT and KO versus vehicle controls. 3) More infection-specific CMPs in WT vs KO AM. 4) When AM from WT and KO vehicle or infected were compared, there were more unique CMPs exclusive to the KO AM. 5) All comparisons showed CMPs shared by both groups.

Conclusions

The decrease of CMPs exclusive to infected AM in KO mice may underlie the observed susceptibility of KO mice to infection. However, both KO groups had more exclusive CMPs than the corresponding WT groups, perhaps indicating a vigorous effort by KO to overcome deficits in certain proteins and CMPs that are dysregulated by the absence of SP-A. Moreover, the presence of shared CMPs in the compared groups indicates that regulation of these CMPs is not dependent on either infection or the presence or absence of SP-A.
Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations
Authors: Ravichandran Ranjithkumar , Bansal Sandhya , Rahman Mohammad , Sureshbabu Angara , Sankpal Narendra , Fleming Timothy , Bharat Ankit , Mohanakumar Thalachallour
Published: April 2022

Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported betweende novosynthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.
T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma
Authors: Wang Jiachen , Shen Kefeng , Mu Wei , Li Weigang , Zhang Meilan , Zhang Wei , Li Zhe , Ge Tong , Zhu Zhoujie , Zhang Shangkun , Chen Caixia , Xing Shugang , Zhu Li , Chen Liting , Wang Na , Huang Liang , Li Dengju , Xiao Min , Zhou Jianfeng
Published: April 2022

Despite impressive progress, a significant portion of patients still experience primary or secondary resistance to chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The mechanism of primary resistance involves T-cell extrinsic and intrinsic dysfunction. In the present study, a total of 135 patients of DLBCL treated with murine CD19/CD22 cocktail CAR T-therapy were assessed retrospectively. Based on four criteria (maximal expansion of the transgene/CAR-positive T-cell levels post-infusion [Cmax], initial persistence of the transgene by the CAR transgene level at +3 months [Tlast], CD19+ B-cell levels [B-cell recovery], and the initial response to CAR T-cell therapy), 48 patients were included in the research and divided into two groups (a T-normal group [n=22] and a T-defect [n=26] group). According to univariate and multivariate regression analyses, higher lactate dehydrogenase (LDH) levels before leukapheresis (hazard ratio (HR) = 1.922; p = 0.045) and lower cytokine release syndrome (CRS) grade after CAR T-cell infusion (HR = 0.150; p = 0.026) were independent risk factors of T-cell dysfunction. Moreover, using whole-exon sequencing, we found that germline variants in 47 genes were significantly enriched in the T-defect group compared to the T-normal group (96% vs. 41%; p<0.0001), these genes consisted of CAR structure genes (n=3), T-cell signal 1 to signal 3 genes (n=13), T cell immune regulation- and checkpoint-related genes (n=9), cytokine- and chemokine-related genes (n=13), and T-cell metabolism-related genes (n=9). Heterozygous germline UNC13D mutations had the highest intergroup differences (26.9% vs. 0%; p=0.008). Compound heterozygous CX3CR1I249/M280 variants, referred to as pathogenic and risk factors according to the ClinVar database, were enriched in the T-defect group (3 of 26). In summary, the clinical characteristics and T-cell immunodeficiency genetic features may help explain the underlying mechanism of treatment primary resistance and provide novel insights into CAR T-cell immunotherapy.
Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study
Authors: Atmar Khaled , Ruivenkamp Claudia A. L. , Hooimeijer Louise , Nibbeling Esther A. R. , Eckhardt Corien L. , Huisman Elise J. , Lankester Arjan C. , Bartels Marije , Santen Gijs W. E. , Smiers Frans J. , van der Burg Mirjam , Mohseny Alexander B.
Published: April 2022

Background

Severe multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).

Methods

We conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.

Results

In 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.

Conclusion

We conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.
Using Radiocarbon Measurements of Dissolved Inorganic Carbon to Determine a Revised Residence Time for Deep Baffin Bay
Authors: Zeidan Sara , Walker Jennifer , Else Brent G. T. , Miller Lisa A. , Azetsu-Scott Kumiko , Walker Brett D.
Published: April 2022

The Canadian Arctic is warming at three times the rate of the rest of the planet and the effects of climate change on the Arctic marine carbon cycle remains unconstrained. Baffin Bay is a semi-enclosed, Arctic basin that connects the Arctic Ocean to the north to the Labrador Sea to the south. While the physical oceanography of surface Baffin Bay is well characterized, less is known about deep water formation mechanisms within the Basin. Only a few residence-time estimates for Baffin Bay Deep Water (BBDW) exist and range from 20 to 1450 years. Better residence time estimates are needed to understand the oceanographic significance of Baffin Bay. Here we report stable carbon (δ13C) and radiocarbon (Δ14C) values of dissolved inorganic carbon (DIC) collected aboard the CCGS Amundsen in 2019. DIC δ13C and Δ14C values between ranged between -0.7‰ to +1.9‰ and -90.0‰ to +29.8‰, respectively. Surface DIC δ13C values were between +0.7‰ to +1.9‰, while deep (>100m) values were 0.0 to -0.7‰. Surface DIC Δ14C values ranged between -5.4‰ to +22.9‰, while deep DIC (>1400m) DIC Δ14C averaged -82.2 ± 8.5‰ (n = 9). To constrain natural DIC Δ14C values, we quantified the amount of atmospheric “bomb” 14C in DIC (Δ14Cbomb; using the potential alkalinity method; Palk) and anthropogenic DIC (DICanth; using the ΔC* method). Both proxies indicate an absence of Δ14Cbomb and DICanth below 1000m. Using two previously proposed deep water formation mechanisms and our corrected DIC Δ14Cnatural values, we estimated a 14C-based residence time of 360-690 years for BBDW. Based on these residence times, we infer carbon is likely stored for centuries in deep Baffin Bay.
Impacts of Morphological Characteristics on Target Strength of Chub Mackerel (Scomber japonicus) in the Northwest Pacific Ocean
Authors: Tong Jianfeng , Xue Minghua , Zhu Zhenhong , Wang Weiqi , Tian Siquan
Published: April 2022

Chub mackerel (Scomber japonicus) is an important commercial fish in the Northwest Pacific Ocean. Accurate target strength (TS) underpins acoustic stock assessment but the TS of S. japonicus is still poorly understood. In this study, the Kirchhoff-ray mode (KRM) model was used to estimate the TS of S. japonicus and its relationship with sound wave frequency and fish morphology. The results revealed that TS values varied with pitch angle shifts, with the impact on fish scattering strength being greater at higher frequency. This is less important because 38 kHz has been used for the biomass assessment of these fish resources. At frequencies of 38 kHz, 70 kHz, 120 kHz and 200 kHz, TS was greatest at a pitch angle range of -10° to 0°, which was related to the angle of the swim bladder tilt. There were almost no differences between TS estimated using the measured pitch angle distributions and using the universal distribution. When the measured pitch angle was N[-3°,4°], the average TS of S. japonicus with body length of 12.04–22.17 cm at four frequencies was -48.88 dB, -49.14 dB, -49.75 dB and -48.55 dB, respectively. The regression intercept (b20) in TS–body length equation was -73.27 dB, -73.56 dB, -74.18 dB and -73.46 dB, respectively. Variation in TS range at 0–300 m depth was about 10 dB. The simulated broadband target strength spectrum shows the scattering characteristics of individuals with different swim bladder length between 0–250 kHz. These results could be used for identification of S. japonicus in echograms and provide reference for acoustic stock assessment of S. japonicus in the Northwest Pacific Ocean.
A Nanoscale Hot-Wire Flow Sensor Based on CMOS-MEMS Technology
Authors: Wang Xiaoyi , Fang Zetao , Song Xiangyu , Xu Wei
Published: April 2022

In this paper, we proposed an ultrafast and nanoscale hot-wire flow (NHF) sensor implemented in a 0.18 µm complementary metal-oxide-semiconductor microelectromechanical system (CMOS-MEMS) technology. The nanoscale wire was released and reduced in thickness and width by an in-house developed post-CMOS fabrication process, hence the heat conduction loss is greatly suppressed, while the response time of the NHF sensor is significantly improved. Benefiting from the nano size of the hot-wire (a width of 622 nm), the NHF sensor exhibits an ultrafast response time of 30 µs (@ airflow velocity of 0 m/s), a wide flow range of 0–30 m/s, and a cut-off frequency of 21 kHz under the constant temperature (CT) mode. In addition, an equivalent circuit model (ECM) was established in PSPICE to predict the NHF sensor performance, and the theoretical simulation results were in good agreement with the experiment results.
What Makes Cirrhosis Irreversible?—Consideration on Structural Changes
Authors: Dezső Katalin , Paku Sándor , Kóbori László , Thorgeirsson Snorri S. , Nagy Péter
Published: April 2022

Several studies have shown that liver fibrosis, and even cirrhosis can be reversed, disproving the old “dogma” that cirrhosis is irreversible. In addition to scaring, vascular alterations appear to be critically important in the progression of chronic liver diseases. To overcome the “tipping-point” of cirrhosis, we need to understand in depth what might make it irreversible in some cases. Morphologically, the initial, as well as the advanced stages of cirrhosis are characterized by specific structural changes. The hallmark of the initial stage is the division of the original liver parenchyma by centro-central or porto-portal septa. No significant vascular changes are observed in this stage. The advanced stage is characterized by several morphological alterations: (i) The main feature is the parenchymal extinction, with intact portal vein branches, hepatic artery branches, and biliary ductules; (ii) In the extinct areas we observed numerous loops in the ductular network, indicating the disruption of the hepato-biliary junctions; (iii) Although the ductular progenitor cells are able to generate hepatocytes via the budding process, the newly formed hepatocyte nodules cannot re-establish the original lobular architecture due to their disorganized growth. In conclusion, this regenerative process characteristic for the advanced stage, contributes to circulatory disorders, perpetuates parenchymal injury and may lead to the irreversibility of cirrhosis.
Hepatocellular Carcinoma: How the Gut Microbiota Contributes to Pathogenesis, Diagnosis, and Therapy
Authors: Luo Wenyu , Guo Shiqi , Zhou Yang , Zhao Jingwen , Wang Mengyao , Sang Lixuan , Chang Bing , Wang Bingyuan
Published: April 2022

The gut microbiota is gaining increasing attention, and the concept of the “gut-liver axis” is gradually being recognized. Leaky gut resulting from injury and/or inflammation can cause the translocation of flora to the liver. Microbiota-associated metabolites and components mediate the activation of a series of signalling pathways, thereby playing an important role in the development of hepatocellular carcinoma (HCC). For this reason, targeting the gut microbiota in the diagnosis, prevention, and treatment of HCC holds great promise. In this review, we summarize the gut microbiota and the mechanisms by which it mediates HCC development, and the characteristic alterations in the gut microbiota during HCC pathogenesis. Furthermore, we propose several strategies to target the gut microbiota for the prevention and treatment of HCC, including antibiotics, probiotics, faecal microbiota transplantation, and immunotherapy.
DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis
Authors: Konopka Anna , Atkin Julie D.
Published: April 2022

DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the “DNA damage response.” Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.
Modeling the Properties of White Matter Tracts Using Diffusion Tensor Imaging to Characterize Patterns of Injury in Aging and Neurodegenerative Disease
Authors: Kok Chun Yen , Lock Christine , Ang Ting Yao , Keong Nicole C.
Published: April 2022

Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that can provide valuable insight into the microstructure of white matter tracts of the brain. In this paper, we evaluated the reliability and reproducibility of deriving a semi-automated pseudo-atlas DTI tractography method vs. standard atlas-based analysis alternatives, for use in clinical cohorts with neurodegeneration and ventriculomegaly. We showed that the semi-automated pseudo-atlas DTI tractography method was reliable and reproducible across different cohorts, generating 97.7% of all tracts. However, DTI metrics obtained from both methods were significantly different across the majority of cohorts and white matter tracts (p < 0.001). Despite this, we showed that both methods produced patterns of white matter injury that are consistent with findings reported in the literature and with DTI profiles generated from these methodologies. Scatter plots comparing DTI metrics obtained from each methodology showed that the pseudo-atlas method produced metrics that implied a more preserved neural structure compared to its counterpart. When comparing DTI metrics against a measure of ventriculomegaly (i.e., Evans’ Index), we showed that the standard atlas-based method was able to detect decreasing white matter integrity with increasing ventriculomegaly, while in contrast, metrics obtained using the pseudo-atlas method were sensitive for stretch or compression in the posterior limb of the internal capsule. Additionally, both methods were able to show an increase in white matter disruption with increasing ventriculomegaly, with the pseudo-atlas method showing less variability and more specificity to changes in white matter tracts near to the ventricles. In this study, we found that there was no true gold-standard for DTI methodologies or atlases. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.
Functional Screening of Parkinson’s Disease Susceptibility Genes to Identify Novel Modulators of α-Synuclein Neurotoxicity in Caenorhabditis elegans
Authors: Vozdek Roman , Pramstaller Peter P. , Hicks Andrew A.
Published: April 2022

Idiopathic Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons during aging. The pathological hallmark of PD is the Lewy body detected in postmortem brain tissue, which is mainly composed of aggregated α-Synuclein (αSyn). However, it is estimated that 90% of PD cases have unknown pathogenetic triggers. Here, we generated a new transgenic Caenorhabditis elegans PD model eraIs1 expressing green fluorescent protein- (GFP-) based reporter of human αSyn in DA neurons, and exhibited a nice readout of the developed αSyn inclusions in DA neurons, leading to their degeneration during aging. Using these animals in a preliminary reverse genetic screening of >100-PD genome-wide association study- (GWAS-) based susceptibility genes, we identified 28 orthologs of C. elegans and their inactivation altered the phenotype of eraIs1; 10 knockdowns exhibited reduced penetrance of αSyn:Venus inclusions formed in the axons of cephalic (CEP) DA neurons, 18 knockdowns exhibited increased penetrance of disrupted CEP dendrite integrity among which nine knockdowns also exhibited disrupted neuronal morphology independent of the expressed αSyn reporter. Loss-of-function alleles of the five identified genes, such as sac-2, rig-6 or lfe-2, unc-43, and nsf-1, modulated the corresponding eraIs1 phenotype, respectively, and supported the RNA interference (RNAi) data. The Western blot analysis showed that the levels of insoluble αSyn:Venus were not correlated with the observed phenotypes in these mutants. However, RNAi of 12 identified modulators reduced the formation of pro-aggregating polyglutamine Q40:YFP foci in muscle cells, suggesting the possible role of these genes in cellular proteotoxicity. Therefore, modulators identified by their associated biological pathways, such as calcium signaling or vesicular trafficking, represent new potential therapeutic targets for neurodegenerative proteopathies and other diseases associated with aging.
Exploring Finger Digit Ratios (2D:4D) in Surgeons, Professional Rugby Players, and Political Journalists to Form a Directional Hypothesis: Could Finger Length Predict Attention and Focus?
Authors: Serpell Benjamin G. , Cook Christian J.
Published: April 2022

In this short report we explore the predictive nature of finger digit ratio (i.e., second/index finger length divided by fourth/ring finger length; 2D:4D) and achievement. This research, with niche and specialized populations, was intended to support and grow on knowledge obtained from other large population 2D:4D studies and help form a directional hypothesis for future work exploring finger digit ratio and “success.” Twenty-nine professional rugby players aged 25.1 ± 4.2 years, height 185.2 ± 6.3 cm and weight 101.9 ± 11.8 kg;n= 16 orthopedic surgeons aged 55.3 ± 9.3 years with height 183.8 ± 10.2 cm and weight 90.8 ± 14.0 kg; andn= 18 political journalists with age, height and weight of 38.8 ± 7.3 years, 182.8 ± 7.8 cm, and 84.4 ± 11.4 kg, respectively, were recruited. Three experiments were conducted where we (1) explored relationships for 2D:4D with testosterone and cortisol responsiveness to low stress exercise, (2) explored relationships for 2D:4D with pupil constriction and pupil constriction latency (pupillometry measures related to testosterone and cortisol responsiveness and to attentiveness), and (3) compared 2D:4D between rugby players, surgeons, and journalists. Our results revealed 2D:4D was not predictive of testosterone and cortisol responsiveness to low-level exercise stress. However, relationships exist for 2D:4D and pupillometry measures (p< 0.05). Journalists right minus left 2D:4D difference was significantly different to rugby players’ and surgeons (p< 0.05). We argue 2D:4D is likely predictive of testosterone sensitivity and associated ability to focus attention; a skill important to high achievement in various contexts.
Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series
Authors: Quintanilla-Bordás Carlos , Gascón-Gimenez Francisco , Alcalá Carmen , Payá María , Mallada Javier , Silla Raquel , Carratalà-Boscà Sara , Gasque-Rubio Raquel , Castillo Jessica , Casanova Bonaventura
Published: April 2022

Introduction

mRNA coronavirus disease 2019 (COVID-19) vaccination has been widely used to arrest the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Rarely, autoimmune events such as relapses in patients with multiple sclerosis (MS) have been reported after vaccination. However, the possible effects of vaccination in a patient already experiencing the symptoms of a relapse represent an unusual scenario that has not been described.

Patients and Methods

This is a retrospective case series of four patients from three major tertiary referral centers that received mRNA COVID-19 vaccination after starting with symptoms of acute demyelination of the central nervous system due to non-recognized MS. A detailed description of each case, including MRI studies, serum light-neurofilament levels, and cerebrospinal fluid (CSF) cytokine profile, is provided.

Case Description

All patients presented exacerbation of ongoing symptoms after vaccination (range 14–112 days first dose). All patients presented MRI features suggestive of highly active MS and fulfilled McDonald 2017 criteria at the time of presentation. All patients presented high serum light-neurofilament levels and oligoclonal G bands restricted to the CSF. Higher levels of interleukin-6 in the CSF were present in the more severe cases.

Discussion

We describe exacerbation of relapses after mRNA COVID-19 vaccination. We hypothesize RNA sensors such as Toll-like receptor 7 may be activated and contribute to amplify the inflammatory response during a relapse.

Conclusion

Patients should seek medical attention if experiencing acute neurological symptoms, especially before vaccination. Fast diagnostic procedures and prompt treatment should be performed in these patients. Pharmacovigilance and further study are warranted to confirm causality.
Open Eyes Increase Neural Oscillation and Enhance Effective Brain Connectivity of the Default Mode Network: Resting-State Electroencephalogram Research
Authors: Wang Yi , Li Jialu , Zeng Lingjing , Wang Haiteng , Yang Tianyi , Shao Yongcong , Weng Xiechuan
Published: April 2022

The default mode network (DMN) has a unique activity pattern in the resting brain. Studies on resting-state brain activity are helpful to identify various brain dynamic characteristics of patients with mental diseases and those of healthy people. The brain produces a series of changes in different eye states. However, the relationship between eye states and the DMN, which is closely related to the resting state, has not been widely examined. This study recruited 42 healthy students aged 17–22. Participants completed the Profile of Mood States questionnaire. Thereafter, the electroencephalogram data was collected with the patients’ eyes open and closed. Changes in neural oscillation and the DMN’s information transmission during different eye openness states were compared. The results showed that the neural oscillation activities of the parietal-occipital network such as the superior parietal lobule and precuneus were significantly enhanced in the eyes open state. In addition, the effective connectivity within the DMN was enhanced during opened eyes, especially from the left precuneus to the left posterior cingulate cortex, and this connectivity was negatively correlated with the Vigor-Activity mood state in the eyes open state. The activity of the DMN in the resting-state is regulated by eye states, which may relate to mood and emotional perception.
Identification of Synaptic DGKθ Interactors That Stimulate DGKθ Activity
Authors: Barber Casey N. , Goldschmidt Hana L. , Ma Qianqian , Devine Lauren R. , Cole Robert N. , Huganir Richard L. , Raben Daniel M.
Published: April 2022

Lipids and their metabolic enzymes are a critical point of regulation for the membrane curvature required to induce membrane fusion during synaptic vesicle recycling. One such enzyme is diacylglycerol kinase θ (DGKθ), which produces phosphatidic acid (PtdOH) that generates negative membrane curvature. Synapses lacking DGKθ have significantly slower rates of endocytosis, implicating DGKθ as an endocytic regulator. Importantly, DGKθ kinase activity is required for this function. However, protein regulators of DGKθ’s kinase activity in neurons have never been identified. In this study, we employed APEX2 proximity labeling and mass spectrometry to identify endogenous interactors of DGKθ in neurons and assayed their ability to modulate its kinase activity. Seven endogenous DGKθ interactors were identified and notably, synaptotagmin-1 (Syt1) increased DGKθ kinase activity 10-fold. This study is the first to validate endogenous DGKθ interactors at the mammalian synapse and suggests a coordinated role between DGKθ-produced PtdOH and Syt1 in synaptic vesicle recycling.
Effect of High-Humidity Hot Air Impingement Steaming on Cistanche deserticola Slices: Drying Characteristics, Weight Loss, Microstructure, Color, and Active Components
Authors: Ai Ziping , Lin Yawen , Xie Yongkang , Mowafy Samir , Zhang Yue , Li Mengjia , Liu Yanhong
Published: April 2022

Cistanche deserticola is one of the most precious herbal medicines and is widely used in the pharmaceutical and healthy food industries. Steaming is an important step prior to drying in the processing of C. deserticola. This research investigated the effects of high-humidity hot air impingement steaming (HHAIS) parameters such as temperature, time, and relative humidity (RH) on drying characteristics, weight loss, color, microstructure, and active components of C. deserticola slices. The results showed that the steaming process caused a weight loss in C. deserticola; however, increasing the RH reduced the weight loss. Starch gelatinization observed from the microstructure of the steamed samples explained their long drying time. The Page model can well fit the drying process with a high R2 (>0.956) under the drying conditions of 60°C and 6 m/s. Steaming increased the content of phenylethanoid glycosides, and the highest content was obtained at 95°C and 60% RH for 20 min, 75°C and 70% RH for 20 min, and 75°C and 60% RH for 30 min. The steamed samples appeared in an oil black color. When the color difference (ΔE) values were in the range of 16.79–20.12, the contents of echinacoside and acteoside reached the maximum. Steaming at 95°C and 60% RH for 20 min, 75°C and 70% RH for 20 min, and 75°C and 60% RH for 30 min are the optimum process conditions. The results from this work provide innovative steaming technology and suitable processing parameters for producing C. deserticola decoction pieces with a high quality, which will broaden its potential application in the functional health food industry.
Physicochemical and Biochemical Evaluation of Amorphous Solid Dispersion of Naringenin Prepared Using Hot-Melt Extrusion
Authors: Ishimoto Kenji , Shimada Yukiko , Ohno Akane , Otani Shuichi , Ago Yukio , Maeda Soya , Lin Bangzhong , Nunomura Kazuto , Hino Nobumasa , Suzuki Masayuki , Nakagawa Shinsaku
Published: April 2022

Naringenin (NRG) is a plant-derived flavonoid. Due to its antioxidant, anti-inflammatory, and analgesic activities it is beneficial to human health and is often used as a functional food ingredient; however, it has poor water solubility and low in vivo bioavailability. Therefore, the efficacy of NRG can be improved by enhancing its water solubility to increase gastrointestinal absorption. Conventional methods for the formulation of NRG are very complex and use toxic organic solvents, making them impractical for the production of functional foods. The objective of this study was to develop a safe and effective NRG-based functional food material. Previously, we established a technology to prepare amorphous solid dispersions (SDs) from functional food ingredients with poor water solubility and used hot-melt extrusion technology that is comparatively simple and does not involve the use of organic solvents. In this study, we prepared NRG SD and evaluated them both physicochemically and biochemically. NRG SD had superior water solubility and gastrointestinal absorption relative to native NRG and showed higher analgesic efficacy in rats than crystalline NRG. NRG SD was administered to mice in a mixed diet for 28 days, and organ weights and hematological/clinical biochemical parameters were assessed. NRG SD did not demonstrate severe adverse effects. The results suggest that NRG SD is a safe and highly efficacious formulation that can be used as a functional food material in the future.
Plant-Based Diets Are Not Enough? Understanding the Consumption of Plant-Based Meat Alternatives Along Ultra-processed Foods in Different Dietary Patterns in Germany
Authors: Ohlau Marlene , Spiller Achim , Risius Antje
Published: April 2022

A low-processive plant-based diet is considered valuable for a sustainable diet profile—it is supposed to meet health as well as environmental concerns. However, there is a growing trend toward plant-based meat alternatives, most of which are to be classified as ultra-processed food (UPF). The paper aimed to understand the consumption of different ultra-processed foods to describe their relation to dietary patterns and sustainability. The objective was (1) to depict the status-quo of consumption of plant-based meat alternatives along with other UPF groups (i.e., convenience products, fast foods, snacks, ultra-processed beverages) in a German sample (n = 814) and (2) to investigate the extent to which all examined UPFs are represented in different dietary patterns (vegetarian, flexitarian, regular meat-eaters, high meat-eaters). UPF intake and dietary groups were determined using a food frequency questionnaire (FFQ). Potential factors influencing UPF consumption, such as attitudes toward sustainability and healthy eating practices, were assessed using validated and fitted psychometric scales. Overall, the frequency of UPF consumption varies significantly along the product groups studied. Plant-based meat alternatives were the least consumed food (12.3%), followed by convenience products (57.4%), fast foods (55.9%), ultra-processed beverages (80.1%), and sweet and salty snacks (97.3%). Plant-based meat alternative consumption predominated within a vegetarian diet, while other UPFs, like convenience products, fast foods, sweet and salty snacks, and ultra-processed beverages, were mainly consumed by meat-eaters. Remarkably, flexitarian diets depict low consumption of all types of ultra-processed foods. In order to meet societal sustainability goals, diets and corresponding societal and political actions should emphasize not only plant orientation but also the increase of non- and low-processed foods.
Paeoniflorin Rescued MK-801-Induced Schizophrenia–Like Behaviors in Mice via Oxidative Stress Pathway
Authors: Liang Jia-Quan , Chen Xi , Cheng Yong
Published: April 2022

Schizophrenia (SCZ) affects approximately 1% population worldwide, and the first-line antipsychotics have partial reactivity or non-reactivity with side effects. Therefore, there is an urgent need to find more effective drugs. Paeoniflorin (PF) is the main effective component of traditional Chinese medicine from white peony, red peony and peony bark, which acts as a neuroprotective agent. The purpose of this study was to investigate whether PF can rescue MK-801 induced schizophrenia-like behavior in mice. Our results demonstrated that intragastric administration of PF ameliorated MK-801 induced schizophrenia–like behaviors in mice as demonstrated by prepulse inhibition of acoustic startle response, fear conditioning test for memory and open field test for activity. In contrast, the first-line antipsychotics-olanzapine reversed the prepulse inhibition deficits and hyperactivities, but not memory deficits, in the model mice. Further analysis showed that PF reduced oxidative stress in the MK-801-treated mice, as evidenced by the increased superoxide dismutase levels and decreased malondialdehyde levels in the blood of the model mice. In addition, PF treatment inhibited the expression of the apoptotic protein Bax and restored the expression of tyrosine hydroxylase in the brains of the model mice. in vitro data indicated that PF protected against oxidative stress induced neurotoxicity in the primary cultured hippocampal neurons. In conclusion, our results were the first to provide evidence that PF rescued schizophrenia-like behaviors (both positive symptoms and cognitive impairments) in rodents through oxidative stress pathway, and therefore provide a novel strategy for treatment of SCZ. However, more pre-clinical and clinical research are needed to translate the present findings into clinics for a treatment of schizophrenia.
Enzymatic Synthesis of Diacylglycerol-Enriched Oil by Two-Step Vacuum-Mediated Conversion of Fatty Acid Ethyl Ester and Fatty Acid From Soy Sauce By-Product Oil as Lipid-Lowering Functional Oil
Authors: Feng Konglong , Fang Huaiyi , Liu Guo , Dai Weijie , Song Mingyue , Fu Jiangyan , Wen Linfeng , Kan Qixin , Chen Yunjiao , Li Yuanyou , Huang Qingrong , Cao Yong
Published: April 2022

Soy sauce by-product oil (SSBO), a by-product of the soy sauce production process, is the lack of utilization due to an abundance of free fatty acid (FFA) and fatty acid ethyl ester (EE). The utilization of low-cost SSBO to produce value-added diacylglycerol (DAG)-enriched oil and its applications are promising for the sustainability of the oil industry. The objective of this study was to utilize SSBO containing a high content of EE and FFA as raw material to synthesize DAG-enriched oil and to evaluate its nutritional properties in fish. Based on different behaviors between the glycerolysis of EE and the esterification of FFA in one-pot enzymatic catalysis, a two-step vacuum-mediated conversion was developed for the maximum conversions of EE and FFA to DAG. After optimization, the maximum DAG yield (66.76%) and EE and FFA conversions (96 and 93%, respectively) were obtained under the following optimized conditions: lipase loading 3%, temperature 38°C, substrate molar ratio (glycerol/FFA and EE) 21:40, a vacuum combination of 566 mmHg within the initial 10 h and 47 mmHg from the 10th to 14th hour. Further nutritional study in fish suggested that the consumption of DAG-enriched oil was safe and served as a functional oil to lower lipid levels in serum and liver, decrease lipid accumulation and increase protein content in body and muscle tissues, and change fatty acid composition in muscle tissues. Overall, these findings were vital for the effective utilization of SSBO resources and the development of future applications for DAG-enriched oil as lipid-lowering functional oil in food.
TBC1D2 Promotes Ovarian Cancer Metastasis via Inducing E-Cadherin Degradation
Authors: Tian Jiming , Liang Xiaolei , Wang Dalin , Tian Jinglin , Liang Haiping , Lei Ting , Yan Zeyu , Wu Dan , Liu Xiaoli , Liu Shujuan , Yang Yongxiu
Published: April 2022

Background

Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide. Increasing evidence indicates that TBC domain family is implicated in various cellular events contributing to initiation and development of different cancers, including OC. However, the role of TBC1D2, a crucial member of TBC domain family, remains unclear in OC.

Methods

IHC and qRT-PCR were employed to determine TBC1D2 expression in OC tissues and cells. In vitro and in vivo assays involving proliferation, migration, invasion were performed to explore the role of TBC1D2 in OC development. The underlying mechanism by which TBC1D2 promotes OC metastasis were elucidated using bioinformatics analysis, western blotting and co-immunoprecipitation.

Results

Upregulation of TBC1D2 was found in OC and was associated with a poor prognosis. Meanwhile, TBC1D2 promoted OC cell proliferation, migration, and invasion in vitro and facilitated tumor growth and metastasis in vivo. Moreover, TBC1D2 contributed to OC cell invasion by E-cadherin degradation via disassembling Rac1-IQGAP1 complex. In addition, miR-373-3p was screened out and identified to inhibit OVCAR3 invasion via negative regulation of TBC1D2.

Conclusion

Our findings indicated that TBC1D2 is overexpressed in OC and contributes to tumor metastasis via E-cadherin degradation. This study suggests that TBC1D2 may be an underlying therapeutic target for OC.
MR-Guided Microwave Ablation for Lung Malignant Tumor: A Single Center Prospective Study
Authors: Lin Ruixiang , Fang Yan , Chen Jin , Lin QingFeng , Chen Jian , Yan Yuan , Chen Jie , Lin Zhengyu
Published: April 2022

Objectives

To prospectively investigate the feasibility and efficacy of MRI-guided MWA for lung malignant tumor in our single center.

Materials and Methods

22 patients [mean age, 56.86 ± 13.05(23–73)years] with 23 malignant lung tumors were enrolled in the study. 21 patients had a single lesion and 1 patient had 2 lesions in the ipsilateral lung. The average maximum diameter of the lesion was 1.26 ± 0.65 (0.50-2.58)cm. Percutaneous MWA was guided by 1.5T MRI scanner using a MR-compatible microwave antenna to the target the lung lesions and ablation area was monitored intraoperatively by using a shielded MR-compatible microwave device and then follow-up.

Results

All patients were successfully treated under MR-guided MWA for lung tumors. Average operation time was 72.21 ± 24.99 (36–158) mins. T2WI signal intensity of the lesion gradually decreased over the course of MWA. The center of the ablated zones showed a short T1 and short T2 signals with the ring-like of long T1 and long T2 signals surrounded after immediately evaluation. No serious complications occurred. The average follow-up period was 12.89 ± 4.33 (2.0-19.6) months. Local recurrence occurred in one patient, representing a technical efficacy of 95.5% (21/22).

Conclusion

Magnetic resonance-guided microwave ablation for lung malignant tumor was feasible and demonstrated unique advantages in efficacy evaluation.