bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers in Medicines Development—From Discovery to Regulatory Qualification and Beyond
Authors: Hendrikse Natalie M. , Llinares Garcia Jordi , Vetter Thorsten , Humphreys Anthony J. , Ehmann Falk
Published: April 2022

Biomarkers are important tools in medicines development and clinical practice. Besides their use in clinical trials, such as for enrichment of patients, monitoring safety or response to treatment, biomarkers are a cornerstone of precision medicine. The European Medicines Agency (EMA) emphasised the importance of the discovery, qualification, and use of biomarkers in their Regulatory Science Strategy to 2025, which included the recommendation to enhance early engagement with biomarker developers to facilitate regulatory qualification. This study explores the journey of biomarkers through the EU regulatory system and beyond, based on a review of interactions between developers and the EMA from 2008 to 2020, as well as the use of qualified biomarkers in clinical trials. Of applicants that used early interaction platforms such as the Innovation Task Force, less than half engaged in fee-related follow-up procedures. Results showed that, as compared to companies, consortia were more likely to opt for the Qualification of Novel Methodologies procedure and engage in follow-up procedures. Our results highlight the importance of early engagement with regulators for achieving biomarker qualification, including pre-submission discussions in the context of the qualification procedure. A review of clinical trials showed that all qualified biomarkers are used in practice, although not always according to the endorsed context of use. Overall, this study highlights important aspects of biomarker qualification, including opportunities to improve the seamless support for developers by EMA. The use of qualified biomarkers in clinical trials underlines the importance of regulatory qualification, which will further enable precision medicine for the benefit of patients.
Evaluation of Performance of Detection of Immunoglobulin G and Immunoglobulin M Antibody Against Spike Protein of SARS-CoV-2 by a Rapid Kit in a Real-Life Hospital Setting
Authors: Irungbam Monica , Chitkara Anubhuti , Singh Vijay Kumar , Sonkar Subash Chandra , Dubey Abhisek , Bansal Aastha , Shrivastava Ritika , Goswami Binita , Manchanda Vikas , Saxena Sonal , Saxena Ritu , Garg Sandeep , Husain Farah , Talukdar Tanmay , Kumar Dinesh , Koner Bidhan Chandra
Published: April 2022

Background

Antibody testing is often used for serosurveillance of coronavirus disease 2019 (COVID-19). Enzyme-linked immunosorbent assay and chemiluminescence-based antibody tests are quite sensitive and specific for such serological testing. Rapid antibody tests against different antigens are developed and effectively used for this purpose. However, their diagnostic efficiency, especially in real-life hospital setting, needs to be evaluated. Thus, the present study was conducted in a dedicated COVID-19 hospital in New Delhi, India, to evaluate the diagnostic efficacy of a rapid antibody kit against the receptor-binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods

Sixty COVID-19 confirmed cases by reverse transcriptase–polymerase chain reaction (RT-PCR) were recruited and categorized as early, intermediate, and late cases based on the days passed after their first RT-PCR–positive test report, with 20 subjects in each category. Twenty samples from pre-COVID era and 20 RT-PCR–negative collected during the study period were taken as controls. immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against the RBD of the spike (S) protein of SARS-CoV-2 virus were detected by rapid antibody test and compared with the total antibody against the nucleocapsid (N) antigen of SARS-CoV-2 by electrochemiluminescence-based immunoassay (ECLIA).

Results

The detection of IgM against the RBD of the spike protein by rapid kit was less sensitive and less specific for the diagnosis of SARS-CoV-2 infection. However, diagnostic efficacy of IgG by rapid kit was highly sensitive and specific when compared with the total antibody against N antigen measured by ECLIA.

Conclusion

It can be concluded that detection of IgM against the RBD of S protein by rapid kit is less effective, but IgG detection can be used as an effective diagnostic tool for SARS-CoV-2 infection in real-life hospital setting.
Proteomic Perspective of Cadmium Tolerance in Providencia rettgeri Strain KDM3 and Its In-situ Bioremediation Potential in Rice Ecosystem
Authors: Salaskar Darshana A. , Padwal Mahesh K. , Gupta Alka , Basu Bhakti , Kale Sharad P.
Published: April 2022

In this study, a multi-metal-tolerant natural bacterial isolate Providencia rettgeri strain KDM3 from an industrial effluent in Mumbai, India, showed high cadmium (Cd) tolerance. Providencia rettgeri grew in the presence of more than 100 ppm (880 μM) Cd (LD50 = 100 ppm) and accumulated Cd intracellularly. Following Cd exposure, a comparative proteome analysis revealed molecular mechanisms underlying Cd tolerance. Among a total of 69 differentially expressed proteins (DEPs) in Cd-exposed cells, de novo induction of ahpCF operon proteins and L-cysteine/L-cystine shuttle protein FliY was observed, while Dps and superoxide dismutase proteins were overexpressed, indicating upregulation of a robust oxidative stress defense. ENTRA1, a membrane transporter showing homology to heavy metal transporter, was also induced de novo. In addition, the protein disaggregation chaperone ClpB, trigger factor, and protease HslU were also overexpressed. Notably, 46 proteins from the major functional category of energy metabolism were found to be downregulated. Furthermore, the addition of P. rettgeri to Cd-spiked soil resulted in a significant reduction in the Cd content [roots (11%), shoot (50%), and grains (46%)] of the rice plants. Cd bioaccumulation of P. rettgeri improved plant growth and grain yield. We conclude that P. rettgeri, a highly Cd-tolerant bacterium, is an ideal candidate for in-situ bioremediation of Cd-contaminated agricultural soils.
Listeria monocytogenes – How This Pathogen Survives in Food-Production Environments?
Authors: Osek Jacek , Lachtara Beata , Wieczorek Kinga
Published: April 2022

The foodborne pathogen Listeria monocytogenes is the causative agent of human listeriosis, a severe disease, especially dangerous for the elderly, pregnant women, and newborns. Although this infection is comparatively rare, it is often associated with a significant mortality rate of 20–30% worldwide. Therefore, this microorganism has an important impact on food safety. L. monocytogenes can adapt, survive and even grow over a wide range of food production environmental stress conditions such as temperatures, low and high pH, high salt concentration, ultraviolet lights, presence of biocides and heavy metals. Furthermore, this bacterium is also able to form biofilm structures on a variety of surfaces in food production environments which makes it difficult to remove and allows it to persist for a long time. This increases the risk of contamination of food production facilities and finally foods. The present review focuses on the key issues related to the molecular mechanisms of the pathogen survival and adaptation to adverse environmental conditions. Knowledge and understanding of the L. monocytogenes adaptation approaches to environmental stress factors will have a significant influence on the development of new, efficient, and cost-effective methods of the pathogen control in the food industry, which is critical to ensure food production safety.
Characterization of Calcium-Dependent Protein Kinase 2A, a Potential Drug Target Against Cryptosporidiosis
Authors: Shu Fanfan , Li Yu , Chu Wenlun , Chen Xuehua , Zhang Ziding , Guo Yaqiong , Feng Yaoyu , Xiao Lihua , Li Na
Published: April 2022

Calcium-dependent protein kinases (CDPKs) are important in calcium influx, triggering several biological processes in Cryptosporidium spp. As they are not present in mammals, CDPKs are considered promising drug targets. Recent studies have characterized CpCDPK1, CpCDPK3, CpCDPK4, CpCDPK5, CpCDPK6, and CpCDPK9, but the role of CpCPK2A remains unclear. In this work, we expressed recombinant CpCDPK2A encoded by the cgd2_1060 gene in Escherichia coli and characterized the biologic functions of CpCDPK2A using qRT-PCR, immunofluorescence microscopy, immuno-electron microscopy, and in vitro neutralization. The results revealed that CpCDPK2A protein was highly expressed in the apical region of sporozoites and merozoites and in macrogamonts. Monoclonal or polyclonal antibodies against CpCDPK2A failed to block the invasion of host cells. Among the 44 candidate inhibitors from molecular docking of CpCDPK2A, one inhibitor was identified as having a potential effect on both Cryptosporidium parvum growth and CpCDPK2A enzyme activities. These data suggest that CpCDPK2A may play some roles during the development of C. parvum and might be a potential drug target against cryptosporidiosis.
Analysis of Key Genes Responsible for Low Urea Production in Saccharomyces cerevisiae JH301
Authors: Liang Zhangcheng , Su Hao , Ren Xiangyun , Lin Xiaozi , He Zhigang , Li Xiangyou , Zheng Yan
Published: April 2022

There is a potential safety risk with ethyl carbamate (EC) in Hongqu Huangjiu production; 90% of the EC in rice wine is produced by the reaction of the urea with the alcohol of Saccharomyces cerevisiae. In our previous experiments, we screened and obtained a S. cerevisiae strain JH301 that offered low urea production. However, the key genes responsible for low urea production of strain JH301 remain unclear. Here, the whole genome sequencing of S. cerevisiae strain JH301 was accomplished via a next-generation high-throughput sequencing and long-read sequencing technology. There are six main pathways related to the urea metabolism of strain JH301 based on KEGG pathway mapping. Three species-specific genes are related to the urea metabolism pathways and were found in comparative genome analysis between strains JH301 and S288c during Hongqu Huangjiu production for the first time. Finally, the ARG80 gene was found to be likely a key gene responsible for low urea production of S. cerevisiae strain JH301, as determined by PCR and qRT-PCR check analyses from DNA and RNA levers. In conclusion, the results are useful for a scientific understanding of the mechanism of low urea production by Saccharomyces cerevisiae during Hongqu Huangjiu fermentation. It also is important to control the urea and EC contents in Hongqu Huangjiu production.
TMPRSS2 Serves as a Prognostic Biomarker and Correlated With Immune Infiltrates in Breast Invasive Cancer and Lung Adenocarcinoma
Authors: Xiao Xinhua , Shan Huizhuang , Niu Yangyang , Wang Peihong , Li Donghe , Zhang Yuyin , Wang Jiayi , Wu Yingli , Jiang Hua
Published: April 2022

TMPRSS2 is a transmembrane serine protease and plays a pivotal role in coronavirus disease 2019 (COVID-19). However, the correlation of TMPRSS2 with prognosis and immune infiltration in tumors has not yet been explored. Here, we analyzed the expression of TMPRSS2 in Oncomine and TIMER databases, the correlation between TMPRSS2 and overall survival in the PrognoScan, Kaplan-Meier plotter, and GEPIA databases. The association between TMPRSS2 and immune infiltration levels was investigated in the TIMER database. In addition, the prognosis of TMPRSS2 related to immune cells in cancers was analyzed. Quantitative real-time PCR (qRT-PCR) confirmed that TMPRSS2 was upregulated in lung adenocarcinoma (LUAD) and downregulated in breast invasive carcinoma (BRCA). We demonstrated that high TMPRSS2 expression was associated with favorable prognosis in LUAD, but it was associated with poor prognosis in BRCA. Interestingly, we found that TMPRSS2 expression was significantly correlated with immune infiltration of B cells, CD4+ T cells, macrophages, and dendritic cells in LUAD, and it was positively correlated with the infiltrating levels of CD8+ T cells, CD4+ T cells, neutrophils, and dendric cells in BRCA. Consistent with the prognosis of TMPRSS2 in LUAD and BRCA, the high expression level of TMPRSS2 has a favorable prognosis in enriched immune cells such as B cells, macrophages, and CD4+ T cells in LUAD, and it has a poor prognosis in CD4+ T cells and CD8+ T cells in BRCA. In conclusion, our results indicate that the prognosis of TMPRSS2 in LUAD and BRCA is significantly correlated with immune cells infiltration. Our study comprehensively revealed the relationship between the prognosis of TMPRSS2 in pan-cancers and tumor immunity.
Effects of the Lipid Metabolites and the Gut Microbiota in ApoE−/− Mice on Atherosclerosis Co-Depression From the Microbiota-Gut-Brain Axis
Authors: Hu Ke , Liao Xing-Xing , Wu Xiao-Yun , Wang Rui , Hu Zi-Wei , Liu Si-Yuan , He Wen-Fen , Zhou Jun-Jie
Published: April 2022

Background: The diagnosis, treatment, and prevention of atherosclerosis co-depression are poor, so it is urgent to explore new targets. Based on the “microbiota-gut-brain axis,” this study aimed to investigate the changes of lipid metabolites in the prefrontal cortex and hippocampus regions and the characteristics of the gut microbiota in ApoE−/− mice with atherosclerosis co-depression.

Methods: ApoE−/− mice (hyperlipid feeding combined with binding, HFB group, n = 14, male) fed a high-fat diet for 16 weeks with binding stimulation were used as an animal model for atherosclerosis co-depression. The depression degree of mice was evaluated by body weight, sucrose preference test, open field test, and tail suspension test. Oil-red O staining, HE staining, and biochemical parameters were used to evaluate the damage degree of atherosclerosis in mice. LC-MS/MS technique for non-targeted lipidomics analysis was used to analyze the differential lipid metabolites in the prefrontal cortex and hippocampus regions of mice. 16S rDNA amplification sequencing was used to screen the differential gut microbial, and association analysis was performed with the differential lipid metabolites.

Results: Compared with the normal control group (NC group), the HFB group showed depression-like behaviors and atherosclerosis-related pathological indicators. The differential lipid metabolites in the prefrontal cortex and hippocampus regions were mainly LPC, LPE, LPS, PC, PE, PS, PI, and GD1a, and were mainly enriched in the glycerophospholipid metabolism pathway and the retrograde endocannabinoid signaling pathway. At the same time, there were significant differences in the structure of the gut microbial community between the two groups. The abundance of Deferribacteres and Proteobacteria in the HFB group increased, while the abundance of Verrucomicrobia and Actinobacteria decreased at the phylum level; the abundance of Desulfovibrio, Clostridium_IV, Helicobacter and Pseudoflavonifractor increased, while the abundance of Akkermansia decreased at the genus level.

Conclusion: Atherosclerosis co-depression of ApoE−/− mice of the prefrontal cortex and hippocampus lipid metabolism pathways of disorder and the changes of to the gut microbiota, which leads to abnormal white matter and synaptic dysfunction, increased gut inflammation, and decreased gut permeability, leading to the release of inflammatory cytokines, there is a strong correlation between both, it further confirmed the existence of the “microbiota-gut-brain axis.”
Pyroptosis-Related Patterns Predict Tumor Immune Landscape and Immunotherapy Response in Bladder Cancer
Authors: Yan Yilin , Cao Xiangqian , Wang Zeyi , Huang Zhengnan , Cai Jinming , Tang Pengfei , Yang Chenkai , Zhang Fang , Xia Shujie , Shen Bing
Published: April 2022

Background: Bladder cancer (BC) is a leading cause of death from malignancy, with significant heterogeneity in the immunotherapeutic responsiveness of advanced status. Pyroptosis, a newly discovered inflammatory programmed cell death, is confirmed to play an indispensable role in tumorigenesis and anti-tumor activity. However, the effect of pyroptosis on the tumor-immune landscape remodeling and immunotherapy in BC remains elusive.

Methods: We comprehensively evaluated the mRNA expression and genomic alterations of 33 pyroptosis-related genes (PRGs) in BC and evaluated the patterns of pyroptosis in publicly available BC datasets. An unsupervised clustering method was used to classify patients into distinct patterns. Then, we established a pyroptosis-related signature score (PS-score) model to quantify the pyroptosis-related patterns of individual BC patients using principal component analysis. Furthermore, we correlated the patterns with the immune landscape and response efficacy of immunotherapy.

Results: Two pyroptosis-related patterns were identified in BC, and distinct patterns showed various immune characteristics. Patterns with a high expression level of PRGs exhibited a survival advantage and showed higher infiltration of cytotoxic lymphocytes. Tumors with a low PS-score were characterized by high tumor-infiltrating lymphocytes and considered “hot.” Further analysis revealed that the PS-score was an independent prognostic factor and could predict the response to immunotherapy for patients with advanced BC. We found a significant positive association between AHNAK2, AHNAK nucleoprotein 2, expression, and PS-score. Functional assays showed that AHNAK2 knockdown was correlated with attenuated invasive ability.

Conclusion: This work comprehensively demonstrated the potential function of pyroptosis-related patterns in the bladder tumor-immune landscape and identified their therapeutic liability in immunotherapy. Our study enhanced our understanding of the immune landscape and provided a new approach toward more effective immunotherapy strategies.
A 13-Gene Signature Based on Estrogen Response Pathway for Predicting Survival and Immune Responses of Patients With UCEC
Authors: Li Yimin , Tian Ruotong , Liu Jiaxin , Ou Chunlin , Wu Qihui , Fu Xiaodan
Published: April 2022

Background: Accumulating evidence suggests that anti-estrogens have been effective against multiple gynecological diseases, especially advanced uterine corpus endometrial carcinoma (UCEC), highlighting the contribution of the estrogen response pathway in UCEC progression. This study aims to identify a reliable prognostic signature for potentially aiding in the comprehensive management of UCEC.

Methods: Firstly, univariate Cox and LASSO regression were performed to identify a satisfying UCEC prognostic model quantifying patients’ risk, constructed from estrogen-response-related genes and verified to be effective by Kaplan-Meier curves, ROC curves, univariate and multivariate Cox regression. Additionally, a nomogram was constructed integrating the prognostic model and other clinicopathological parameters. Next, UCEC patients from the TCGA dataset were divided into low- and high-risk groups according to the median risk score. To elucidate differences in biological characteristics between the two risk groups, pathway enrichment, immune landscape, genomic alterations, and therapeutic responses were evaluated to satisfy this objective. As for treatment, effective responses to anti-PD-1 therapy in the low-risk patients and sensitivity to six chemotherapy drugs in the high-risk patients were demonstrated.

Results: The low-risk group with a relatively favorable prognosis was marked by increased immune cell infiltration, higher expression levels of HLA members and immune checkpoint biomarkers, higher tumor mutation burden, and lower copy number alterations. This UCEC prognostic signature, composed of 13 estrogen-response-related genes, has been identified and verified as effective.

Conclusion: Our study provides molecular signatures for further functional and therapeutic investigations of estrogen-response-related genes in UCEC and represents a potential systemic approach to characterize key factors in UCEC pathogenesis and therapeutic responses.
Peroxisome Proliferator–Activated Receptor-α: A Pivotal Regulator of the Gastrointestinal Tract
Authors: Guo Yue-Xin , Wang Bo-Ya , Gao Han , Hua Rong-Xuan , Gao Lei , He Cheng-Wei , Wang Ying , Xu Jing-Dong
Published: April 2022

Peroxisome proliferator–activated receptor (PPAR)-α is a ligand-activated transcription factor distributed in various tissues and cells. It regulates lipid metabolism and plays vital roles in the pathology of the cardiovascular system. However, its roles in the gastrointestinal tract (GIT) are relatively less known. In this review, after summarizing the expression profile of PPAR-α in the GIT, we analyzed its functions in the GIT, including physiological control of the lipid metabolism and pathologic mediation in the progress of inflammation. The mechanism of this regulation could be achievedviainteractions with gut microbes and further impact the maintenance of body circadian rhythms and the secretion of nitric oxide. These are also targets of PPAR-α and are well-described in this review. In addition, we also highlighted the potential use of PPAR-α in treating GIT diseases and the inadequacy of clinical trials in this field.
Perspective: Biochemical and Physical Constraints Associated With Preparing Thin Specimens for Single-Particle Cryo-EM
Authors: Han Bong-Gyoon , Armstrong Max , Fletcher Daniel A. , Glaeser Robert M.
Published: April 2022

While many aspects of single-particle electron cryo-microscopy (cryo-EM) of biological macromolecules have reached a sophisticated level of development, this is not yet the case when it comes to preparing thin samples on specimen grids. As a result, there currently is considerable interest in achieving better control of both the sample thickness and the amount of area that is useful, but this is only one aspect in which improvement is needed. This Perspective addresses the further need to prevent the macromolecular particles from making contact with the air-water interface, something that can result in preferential orientation and even structural disruption of macromolecular particles. This unwanted contact can occur either as the result of free diffusion of particles during the interval between application, thinning and vitrification of the remaining buffer, or—when particles have been immobilized—by the film of buffer becoming too thin prior to vitrification. An opportunity now exists to apply theoretical and practical insights from the fields of thin-film physical chemistry and interfacial science, in an effort to bring cryo-EM sample preparation to a level of sophistication that is comparable to that of current data collection and analysis.
Functional and Structural Diversity of Bacterial Contact-Dependent Growth Inhibition Effectors
Authors: Cuthbert Bonnie J. , Hayes Christopher S. , Goulding Celia W.
Published: April 2022

Bacteria live in complex communities and environments, competing for space and nutrients. Within their niche habitats, bacteria have developed various inter-bacterial mechanisms to compete and communicate. One such mechanism is contact-dependent growth inhibition (CDI). CDI is found in many Gram-negative bacteria, including several pathogens. These CDI+ bacteria encode a CdiB/CdiA two-partner secretion system that delivers inhibitory toxins into neighboring cells upon contact. Toxin translocation results in the growth inhibition of closely related strains and provides a competitive advantage to the CDI+ bacteria. CdiB, an outer-membrane protein, secretes CdiA onto the surface of the CDI+ bacteria. When CdiA interacts with specific target-cell receptors, CdiA delivers its C-terminal toxin region (CdiA-CT) into the target-cell. CdiA-CT toxin proteins display a diverse range of toxic functions, such as DNase, RNase, or pore-forming toxin activity. CDI+ bacteria also encode an immunity protein, CdiI, that specifically binds and neutralizes its cognate CdiA-CT, protecting the CDI+ bacteria from auto-inhibition. In Gram-negative bacteria, toxin/immunity (CdiA-CT/CdiI) pairs have highly variable sequences and functions, with over 130 predicted divergent toxin/immunity complex families. In this review, we will discuss biochemical and structural advances made in the characterization of CDI. This review will focus on the diverse array of CDI toxin/immunity complex structures together with their distinct toxin functions. Additionally, we will discuss the most recent studies on target-cell recognition and toxin entry, along with the discovery of a new member of the CDI loci. Finally, we will offer insights into how these diverse toxin/immunity complexes could be harnessed to fight human diseases.
Relevance of Amorphous and Amyloid-Like Aggregates of the p53 Core Domain to Loss of its DNA-Binding Activity
Authors: Hibino Emi , Tenno Takeshi , Hiroaki Hidekazu
Published: April 2022

The anti-oncogenic protein p53 is a transcription factor that prevents tumorigenesis by inducing gene repair proteins or apoptosis under DNA damage. Since the DNA-binding domain of p53 (p53C) is aggregation-prone, the anti-oncogenic function of p53 is often lost in cancer cells. This tendency is rather severe in some tumor-related p53 mutants, such as R175H. In this study, we examined the effect of salts, including KCl and sugars, on the aggregation of p53C by monitoring two distinct aggregates: amorphous-like and amyloid-like. The amorphous aggregates are detectable with 8-(phenylamino)-1-naphthalenesulfonic acid (ANS) fluorescence, whereas the amyloid aggregates are sensitive to thioflavin-T (ThT) fluorescence. We found that KCl inhibited the formation of amorphous aggregates but promoted the formation of amyloid aggregates in a p53C R175H mutant. The salts exhibited different effects against the wild-type and R175H mutants of p53C. However, the ratio of ANS/ThT fluorescence for the wild-type and R175H mutant remained constant. KCl also suppressed the structural transition and loss of the DNA-binding function of p53C. These observations indicate the existence of multiple steps of p53C aggregation, probably coupled with the dissociation of Zn. Notably, amorphous aggregates and amyloid aggregates have distinct properties that could be discriminated by various small additives upon aggregation.
Evidence That Nine Autistic Women Out of Ten Have Been Victims of Sexual Violence
Authors: Cazalis Fabienne , Reyes Elisabeth , Leduc Séverine , Gourion David
Published: April 2022

Background

Research indicates that sexual violence affects about 30% of women in the general population and between two to three times as much for autistic women.

Materials and Methods

We investigated prevalence of sexual abuse, autistic traits and a range of symptoms, using an online survey addressed to the women of the French autistic community (n = 225). We assessed victimization through an open question and through a specific questionnaire, derived from the Sexual Experiences Survey-Short Form Victimization.

Results

Both case identification methods yielded high figures: 68.9% victimization (open question) compared to 88.4% (standardized questionnaire). Two thirds of the victims were very young when they were first assaulted: among 199 victims, 135 were aged 18 or below and 112 participants were aged 15 or below. 75% of participants included in our study reported several aggressions. Analyses indicate that primo-victimization was highly correlated to revictimization and that being young increased that risk. Young victims were also at higher risk of developing post-traumatic stress disorder. A third of the victims reported the assault. 25% of those were able to file a complaint (n = 12) and/or receive care (n = 13). For the remainder 75%, reporting did not lead to action.

Discussion

Those findings indicate a very large proportion of victims of sexual assault among autistic women, consistently with previous research. The World Health Organization states unambiguously that sexual violence is systemic and that vulnerable individuals are preferably targeted by offenders. We therefore postulate that it would be erroneous to consider that victimization of autistic women is mainly due to autism. On the contrary, autism seems to be just a vulnerability factor. Some authors propose that educating potential victims to better protect themselves would help preventing abuse. We reviewed this proposition in the light of our results and found it to be impossible to apply since more than half of the victims were below or at the age of consent. Literature about sexual violence is discussed. Large-scale prevention programs proposed by World Health Organization and the Center for Disease Control aim at cultural changes in order to diminish gender inequality, that they identify as the very root of sexual violence.
Neuroanatomical Basis for the Orexinergic Modulation of Anesthesia Arousal and Pain Control
Authors: Xiang Xuaner , Chen Yuzhang , Li Ke-Xin , Fang Jianqiao , Bickler Philip E. , Guan Zhonghui , Zhou Wei
Published: April 2022

Hypothalamic orexin (hypocretin) neurons play crucial roles in arousal control. Their involvement in anesthesia and analgesia remains to be better understood. In order to enhance our view on the neuroanatomy, we systematically mapped the projections of orexin neurons with confocal microscope and light sheet microscope. We specifically expressed optogenetic opsins tagged with fluorescence markers in orexin neurons through adeno-associated viral infection in the mouse brain. The imaging results revealed fine details and novel features of the orexin projections throughout the brain, particularly related to the nuclei regulating arousal and pain. We then optogenetically activated orexin neurons in the lateral hypothalamus to study the effects on anesthesia-related behaviors. cFos staining showed that optogenetic stimulation can activate orexin neurons in the ChR2-mCherry group, but not the control mCherry group (62.86 ± 3.923% vs. 7.9 ± 2.072%; P < 0.0001). In behavior assays, optogenetic stimulation in the ChR2-mCherry group consistently elicited robust arousal from light isoflurane anesthesia (9.429 ± 3.804 s vs. 238.2 ± 17.42 s; P < 0.0001), shortened the emergence time after deep isoflurane anesthesia (109.5 ± 13.59 s vs. 213.8 ± 21.77 s; P = 0.0023), and increased the paw withdrawal latency in a hotplate test (11.45 ± 1.185 s vs. 8.767 ± 0.7775; P = 0.0317). The structural details of orexin fibers established the neuroanatomic basis for studying the role of orexin in anesthesia and analgesia.
A Peri-Ictal EEG-Based Biomarker for Sudden Unexpected Death in Epilepsy (SUDEP) Derived From Brain Network Analysis
Authors: Tufa Uilki , Gravitis Adam , Zukotynski Katherine , Chinvarun Yotin , Devinsky Orrin , Wennberg Richard , Carlen Peter L. , Bardakjian Berj L.
Published: April 2022

Sudden unexpected death in epilepsy (SUDEP) is the leading seizure-related cause of death in epilepsy patients. There are no validated biomarkers of SUDEP risk. Here, we explored peri-ictal differences in topological brain network properties from scalp EEG recordings of SUDEP victims. Functional connectivity networks were constructed and examined as directed graphs derived from undirected delta and high frequency oscillation (HFO) EEG coherence networks in eight SUDEP and 14 non-SUDEP epileptic patients. These networks were proxies for information flow at different spatiotemporal scales, where low frequency oscillations coordinate large-scale activity driving local HFOs. The clustering coefficient and global efficiency of the network were higher in the SUDEP group pre-ictally, ictally and post-ictally (p < 0.0001 to p < 0.001), with features characteristic of small-world networks. These results suggest that cross-frequency functional connectivity network topology may be a non-invasive biomarker of SUDEP risk.
Psychoanalytical Considerations of Emotion Regulation Disorders in Multiple Complex-Traumatized Children—A Study Protocol of the Prospective Study MuKi
Authors: Hug Felicitas , Degen Tom , Meurs Patrick , Fischmann Tamara
Published: April 2022

Studies in adults with mental disorders suggest that the experience of early and chronic trauma is associated with changes in reward expectancy and processing. In addition, severe childhood trauma has been shown to contribute to the development of mental disorders in general. Data on effects of early childhood trauma on reward expectancy and processing in middle childhood currently appear insufficient. The present study aims to fill this research gap by examining the effects of developmental trauma disorder (DTD) on reward expectancy and processing in children aged 8–12 years, testing the hypothesis that children with multiple complex traumas exhibit altered reward processing as a result of prior disappointing reward experiences. One main feature of developmental trauma disorder is early experiences of multiple separation from important and close relationships alongside other experiences of emotional or physical harm. In the sequel children often show affect regulation disorders. To investigate this, we have developed an adapted version of the Monetary Incentive Delay (MID) Task, which examines children’s expectation of reward or frustration. In this first study, behavioral data will be collected from N = 40 children (n = 20 experimental group and n = 20 healthy controls) using this adapted version of the MID Task. Children in the experimental group will be recruited from youth welfare centers in Frankfurt a.M., Germany. Healthy control subjects will be recruited from after-school-care facilities. A brief trauma screening will be conducted for both groups, experimental and control. If children show signs of trauma, the presence of a developmental trauma disorder will be further delineated by a German translation of the Developmental Trauma Disorder Structured Interview for Children (DTDSI-C) which was translated the first time in German by our research group. We hypothesize that children in the experimental group will be less accurate in performing the Monetary Incentive Delay Task because of their impaired emotion regulation skills due to emotional avoidance following developmental trauma. If the results of our initial behavioral study are promising, the MID task will be used in a future study to elucidate the relationship between trauma developmental disorder, reward expectancy and processing, and neurobiological processes in middle childhood.
Roles for Mitochondrial Complex I Subunits in Regulating Synaptic Transmission and Growth
Authors: Mallik Bhagaban , Frank C. Andrew
Published: April 2022

To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function and plasticity by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (300 Drosophila lines screened). From our screen, knockdown of a Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. We localized this neurotransmission function to the muscle. Pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns or pharmacological inhibition led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinson’s disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.
Regional Neural Activity Abnormalities and Whole-Brain Functional Connectivity Reorganization in Bulimia Nervosa: Evidence From Resting-State fMRI
Authors: Wang Jia-ni , Tang Li-rong , Li Wei-hua , Zhang Xin-yu , Shao Xiao , Wu Ping-ping , Yang Ze-mei , Wu Guo-wei , Chen Qian , Wang Zheng , Zhang Peng , Li Zhan-jiang , Wang Zhenchang
Published: April 2022

The management of eating behavior in bulimia nervosa (BN) patients is a complex process, and BN involves activity in multiple brain regions that integrate internal and external functional information. This functional information integration occurs in brain regions involved in reward, cognition, attention, memory, emotion, smell, taste, vision and so on. Although it has been reported that resting-state brain activity in BN patients is different from that of healthy controls, the neural mechanisms remain unclear and need to be further explored. The fractional amplitude of low-frequency fluctuation (fALFF) analyses are an important data-driven method that can measure the relative contribution of low-frequency fluctuations within a specific frequency band to the whole detectable frequency range. The fALFF is well suited to reveal the strength of interregional cooperation at the single-voxel level to investigate local neuronal activity power. FC is a brain network analysis method based on the level of correlated dynamics between time series, which establishes the connection between two spatial regions of interest (ROIs) with the assistance of linear temporal correlation. Based on the psychological characteristics of patients with BN and the abnormal brain functional activities revealed by previous neuroimaging studies, in this study, we investigated alterations in regional neural activity by applying fALFF analysis and whole-brain functional connectivity (FC) in patients with BN in the resting state and to explore correlations between brain activities and eating behavior. We found that the left insula and bilateral inferior parietal lobule (IPL), as key nodes in the reorganized resting-state neural network, had altered FC with other brain regions associated with reward, emotion, cognition, memory, smell/taste, and vision-related functional processing, which may have influenced restrained eating behavior. These results could provide a further theoretical basis and potential effective targets for neuropsychological treatment in patients with BN.
Uncertainty-Aware and Lesion-Specific Image Synthesis in Multiple Sclerosis Magnetic Resonance Imaging: A Multicentric Validation Study
Authors: Finck Tom , Li Hongwei , Schlaeger Sarah , Grundl Lioba , Sollmann Nico , Bender Benjamin , Bürkle Eva , Zimmer Claus , Kirschke Jan , Menze Björn , Mühlau Mark , Wiestler Benedikt
Published: April 2022

Generative adversarial networks (GANs) can synthesize high-contrast MRI from lower-contrast input. Targeted translation of parenchymal lesions in multiple sclerosis (MS), as well as visualization of model confidence further augment their utility, provided that the GAN generalizes reliably across different scanners. We here investigate the generalizability of a refined GAN for synthesizing high-contrast double inversion recovery (DIR) images and propose the use of uncertainty maps to further enhance its clinical utility and trustworthiness. A GAN was trained to synthesize DIR from input fluid-attenuated inversion recovery (FLAIR) and T1w of 50 MS patients (training data). In another 50 patients (test data), two blinded readers (R1 and R2) independently quantified lesions in synthetic DIR (synthDIR), acquired DIR (trueDIR) and FLAIR. Of the 50 test patients, 20 were acquired on the same scanner as training data (internal data), while 30 were scanned at different scanners with heterogeneous field strengths and protocols (external data). Lesion-to-Background ratios (LBR) for MS-lesions vs. normal appearing white matter, as well as image quality parameters were calculated. Uncertainty maps were generated to visualize model confidence. Significantly more MS-specific lesions were found in synthDIR compared to FLAIR (R1: 26.7 ± 2.6 vs. 22.5 ± 2.2 p < 0.0001; R2: 22.8 ± 2.2 vs. 19.9 ± 2.0, p = 0.0005). While trueDIR remained superior to synthDIR in R1 [28.6 ± 2.9 vs. 26.7 ± 2.6 (p = 0.0021)], both sequences showed comparable lesion conspicuity in R2 [23.3 ± 2.4 vs. 22.8 ± 2.2 (p = 0.98)]. Importantly, improvements in lesion counts were similar in internal and external data. Measurements of LBR confirmed that lesion-focused GAN training significantly improved lesion conspicuity. The use of uncertainty maps furthermore helped discriminate between MS lesions and artifacts. In conclusion, this multicentric study confirms the external validity of a lesion-focused Deep-Learning tool aimed at MS imaging. When implemented, uncertainty maps are promising to increase the trustworthiness of synthetic MRI.
Acupuncture Modulates the Spontaneous Activity and Functional Connectivity of Calcarine in Patients With Chronic Stable Angina Pectoris
Authors: Lan Lei , Yin Tao , Tian Zilei , Lan Ying , Sun Ruirui , Li Zhengjie , Jing Miaomiao , Wen Qiao , Li Shenghong , Liang Fanrong , Zeng Fang
Published: April 2022

Background

Acupuncture is an effective adjunctive therapy for chronic stable angina pectoris (CSAP), while the underlying mechanism is unclear. This study aimed to investigate the central pathophysiology of CSAP and explore the mechanism of different acupoint prescriptions for CSAP from the perspective of brain-heart interaction.

Methods

Thirty-seven CSAP patients and sixty-five healthy subjects (HS) were enrolled, and thirty CSAP patients were divided into two acupoint prescriptions groups (Group A: acupoints on the meridian directly related to the Heart; Group B: acupoints on the meridian indirectly related to the Heart). The Magnetic Resonance Imaging data and clinical data were collected at baseline and after treatment. The comparisons of brain spontaneous activity patterns were performed between CSAP patients and HS, as well as between baseline and after treatment in CSAP patients. Then, the changes in resting-state functional connectivity before and after treatment were compared between the two acupoint prescriptions.

Results

Chronic stable angina pectoris patients manifested higher spontaneous activity on the bilateral calcarine, left middle occipital gyrus, right superior temporal gyrus, and right postcentral gyrus. After acupuncture treatment, the spontaneous activity of the left calcarine, left cuneus, and right orbitofrontal gyrus was decreased. The left calcarine was identified as region-of-interest for functional connectivity analysis. Compared with group B, CSAP patients in group A had significantly increased functional connectivity between left calcarine and the left inferior temporal gyrus/cerebellum crus 1, left hippocampus, left thalamus, and left middle cingulate cortex after treatment. Thresholds for all comparisons were p < 0.05, Gaussian Random Field corrected.

Conclusion

Regulating the aberrant spontaneous activity of the calcarine might be an underlying mechanism of acupuncture for CSAP. The multi-threaded modulation of functional connectivity between calcarine and multiple pain-related brain regions might be a potential mechanism for better efficacy of acupuncture at points on the meridian directly related to the Heart.
Determination of the Effects of Duodenal Infusion Soy Protein Hydrolysate on Hepatic Glucose and Lipid Metabolism in Pigs Through Multi-Omics Analysis
Authors: Li Zhongxin , Ding Liren , Zhu Weiyun , Hang Suqin
Published: April 2022

High animal protein intake increases hepatic lipid deposition and the risk of diabetes. However, the effects of high plant protein (HPP) intake on glycaemic responses and hepatic lipid metabolism in healthy people, as well as the underlying mechanisms, remain unclear. The current study explored the metabolomic and transcriptomic responses in the livers of pigs to assess the effects of HPP intake on host glucose and lipid metabolism. Sixteen pigs were infused with sterile saline or soy protein hydrolysate (SPH; 70 g/day) through a duodenal fistula twice daily during a 15 days experimental period. Hepatic metabolomic and transcriptomic analyses were performed, and the serum and hepatic biochemical parameters were measured. The results revealed that SPH infusion decreased serum glucose, hepatic triglyceride (TG), total cholesterol and low-density lipoprotein cholesterol levels, while it increased serum urea and eight hepatic amino acid levels (P < 0.05). Hepatic metabolomics displayed that SPH treatment produced seven different metabolites, four of which were related to lipid metabolism and one was related to glucose metabolism. In particular, lower (P < 0.05) glycocholic acid and glucose 1-phosphate levels and higher (P < 0.05) phosphatidylethanolamine (PE), arachidonic acid, prostaglandin F2α, l-carnitine and indole-3 acetic acid levels were observed following SPH infusion. A further metabolic pathway enrichment analysis found that these differential metabolites were mainly enriched in pathways related to lipid and glucose metabolism. Hepatic transcriptomics also demonstrated that multiple genes related to glucose and lipid metabolism were affected by SPH (P < 0.05). Together, SPH infusion reduced the hepatic TG levels by accelerating fatty acid β-oxidation and inhibiting TG synthesis. In addition, SPH infusion reduced the serum glucose levels by promoting hepatic glucose uptake and glycolysis. This study's result demonstrated that HPP intake regulated glycaemic responses and hepatic lipid metabolism in pigs without increasing the risk of hepatic lipid deposition and hyperglycaemia.
Effects of Buffalo Milk and Cow Milk on Lipid Metabolism in Obese Mice Induced by High Fat
Authors: Jiang Maocheng , Meng Zitong , Cheng Zhiqiang , Zhan Kang , Ma Xiaoyu , Yang Tianyu , Huang Yinghao , Yan Qi , Gong Xiaoxiao , Zhao Guoqi
Published: April 2022

The aim of this study was to evaluate the effects of buffalo milk and cow milk on lipid metabolism in obese mice. Milk composition analysis showed fat, protein, and total solid content in buffalo milk was higher than cow milk, while the lactose content of buffalo milk was lower than cow milk. After milk metabolite extraction and LC-MS/MS analysis, differential metabolites were mainly enriched in “linoleic acid metabolism pathways,” “pentose and glucuronate interconversion pathways,” and “metabolism of xenobiotics by cytochrome P450 pathways.” We fed three groups of C57BL/6J mice (n = 6 per group) for 5 weeks: (1) high-fat diet group (HFD group); (2) high-fat diet + buffalo milk group (HBM group); and (3) high-fat diet + cow milk group (HCM group). Our results showed that body weight of mice was significantly decreased in HBM and HCM groups from 1 to 4 weeks compared with the HFD group. The mRNA expression of ACAA2, ACACB, and SLC27A5 genes involved in the lipid metabolism in liver tissue were significantly elevated in HCM group, relatively to HFD and HBM group. In addition, the adipocyte number, size and lipid accumulation in the liver were significantly decreased in HCM group compared with the HFD group by H&E staining and oil red O staining, but was not change in HBM group. The mRNA levels of TNF-α and IL-1β inflammatory genes were significantly increased in HBM group, relatively to HFD and HCM group, which is consistent with results from inflammatory cell infiltration and tissue disruption by colon tissue sections. In conclusion, dietary supplementation of cow milk has beneficial effects on loss of weight and lipid metabolism in obese mice.