bluuebunny/crossref_metadata_2025 huggingface dataset:
Pi-Dan-Jian-Qing Decoction Ameliorates Type 2 Diabetes Mellitus Through Regulating the Gut Microbiota and Serum Metabolism
Authors: Xie Xuehua , Liao Jiabao , Ai Yuanliang , Gao Jinmei , Zhao Jie , Qu Fei , Xu Chao , Zhang Zhaiyi , Wen Weibo , Cui Huantian , Wang Hongwu
Published: December 2021

Pi-Dan-Jian-Qing decoction (PDJQ) can been used in the treatment of type 2 diabetes mellitus (T2DM) in clinic. However, the protective mechanisms of PDJQ on T2DM remain unknown. Recent studies have shown that the changes in gut microbiota could affect the host metabolism and contribute to progression of T2DM. In this study, we first investigated the therapeutic effects of PDJQ on T2DM rats. 16S rRNA sequencing and untargeted metabolomics analyses were used to investigate the mechanisms of action of PDJQ in the treatment of T2DM. Our results showed that PDJQ treatment could improve the hyperglycemia, hyperlipidemia, insulin resistance (IR) and pathological changes of liver, pancreas, kidney, and colon in T2DM rats. PDJQ could also decrease the levels of pro-inflammatory cytokines and inhibit the oxidative stress. 16S rRNA sequencing showed that PDJQ could decrease the Firmicutes/Bacteroidetes (F to B) ratio at the phylum level. At the genus level, PDJQ could increase the relative abundances of Lactobacillus, Blautia, Bacteroides, Desulfovibrio and Akkermansia and decrease the relative abundance of Prevotella. Serum untargeted metabolomics analysis showed that PDJQ could regulate tryptophan metabolism, histidine metabolism, tricarboxylic acid (TCA) cycle, phenylalanine, tyrosine and tryptophan biosynthesis and tyrosine metabolism pathways. Correlation analysis indicated that the modulatory effects of PDJQ on the tryptophan metabolism, histidine metabolism and TCA cycle pathways were related to alterations in the abundance of Lactobacillus, Bacteroides and Akkermansia. In conclusion, our study revealed the various ameliorative effects of PDJQ on T2DM, including improving the liver and kidney functions and alleviating the hyperglycemia, hyperlipidemia, IR, pathological changes, oxidative stress and inflammatory response. The mechanisms of PDJQ on T2DM are likely linked to an improvement in the dysbiosis of gut microbiota and modulation of tryptophan metabolism, histamine metabolism, and the TCA cycle.
A Volatile and Dynamic Longitudinal Microbiome Is Associated With Less Reduction in Lung Function in Adolescents With Cystic Fibrosis
Authors: Metzger Marisa I. , Graeber Simon Y. , Stahl Mirjam , Sommerburg Olaf , Mall Marcus A. , Dalpke Alexander H. , Boutin Sébastien
Published: December 2021

Progressive impairment in lung function caused by chronic polymicrobial airway infection remains the major cause of death in patients with cystic fibrosis (CF). Cross-sectional studies suggest an association between lung function decline and specific lung microbiome ecotypes. However, longitudinal studies on the stability of the airway microbiome are missing for adolescents with CF constituting the age group showing the highest rate of decline in lung function. In this study, we analyzed longitudinal lung function data and sputum samples collected over a period of 3 to 5 years from 12 adolescents with CF. The sputum microbiome was analyzed using 16S rRNA gene sequencing. Our results indicate that the individual course of the lung microbiome is associated with longitudinal lung function. In our cohort, patients with a dynamic, diverse microbiome showed a slower decline of lung function measured by FEV1% predicted, whereas a more stable and less diverse lung microbiome was related to worse outcomes. Specifically, a higher abundance of the phyla Bacteroidetes and Firmicutes was linked to a better clinical outcome, while Proteobacteria were correlated with a decline in FEV1% predicted. Our study indicates that the stability and diversity of the lung microbiome and the abundance of Bacteroidetes and Firmicutes are associated with the lung function decline and are one of the contributing factors to the disease severity.
An Evaluation of Speech-Based Recognition of Emotional and Physiological Markers of Stress
Authors: Baird Alice , Triantafyllopoulos Andreas , Zänkert Sandra , Ottl Sandra , Christ Lukas , Stappen Lukas , Konzok Julian , Sturmbauer Sarah , Meßner Eva-Maria , Kudielka Brigitte M. , Rohleder Nicolas , Baumeister Harald , Schuller Björn W.
Published: December 2021

Life in modern societies is fast-paced and full of stress-inducing demands. The development of stress monitoring methods is a growing area of research due to the personal and economic advantages that timely detection provides. Studies have shown that speech-based features can be utilised to robustly predict several physiological markers of stress, including emotional state, continuous heart rate, and the stress hormone, cortisol. In this contribution, we extend previous works by the authors, utilising three German language corpora including more than 100 subjects undergoing a Trier Social Stress Test protocol. We present cross-corpus and transfer learning results which explore the efficacy of the speech signal to predict three physiological markers of stress—sequentially measured saliva-based cortisol, continuous heart rate as beats per minute (BPM), and continuous respiration. For this, we extract several features from audio as well as video and apply various machine learning architectures, including a temporal context-based Long Short-Term Memory Recurrent Neural Network (LSTM-RNN). For the task of predicting cortisol levels from speech, deep learning improves on results obtained by conventional support vector regression—yielding a Spearman correlation coefficient (ρ) of 0.770 and 0.698 for cortisol measurements taken 10 and 20 min after the stress period for the two corpora applicable—showing that audio features alone are sufficient for predicting cortisol, with audiovisual fusion to an extent improving such results. We also obtain a Root Mean Square Error (RMSE) of 38 and 22 BPM for continuous heart rate prediction on the two corpora where this information is available, and a normalised RMSE (NRMSE) of 0.120 for respiration prediction (−10: 10). Both of these continuous physiological signals show to be highly effective markers of stress (based on cortisol grouping analysis), both when available as ground truth and when predicted using speech. This contribution opens up new avenues for future exploration of these signals as proxies for stress in naturalistic settings.
Case Report: Cardiac Toxicity Associated With Immune Checkpoint Inhibitors
Authors: Chen Ru , Peng Ling , Qiu Zhihua , Wang Yan , Wei Fen , Zhou Min , Zhu Feng
Published: December 2021

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancer. Along with the development of ICIs, immune-related adverse effects (irAEs) have been the subject of wide attention. The cardiac irAE, a rare but potentially fatal and fulminant effect, have been reported recently. This article retrospectively reviewed 10 cases from our hospital with cardiac irAEs, with severity ranging from asymptomatic troponin-I elevations to cardiac conduction abnormalities and even fulminant myocarditis. In our series, all the cases were solid tumors and lung cancer was the most frequent cancer type (4,40%). In total, three (30.0%) patients experienced more than one type of life-threatening complication. A systemic corticosteroid was given to nine patients (90.0%). The majority of cases (7, 70%) were performed at an initial dose of 1–2 mg/kg/day. Two (20.0%) patients were admitted to ICU, three (30.0%) patients were put on mechanical ventilation, two (20.0%) patients received the plasma exchange therapy, and one patient was implanted with a pacemaker. Two (20.0%) of the patients succumbed and died, with a median duration of 7.5 days (IQR5.0–10.0) from diagnosis of cardiac irAE to death. Based on these results, we recommend that clinicians be alert to cardiac irAEs, including performing cardiovascular examinations before ICI treatment to accurately diagnose suspected myocarditis, enabling immediate initiation of immunosuppressive therapy to improve prognosis.
Listening to Mental Health Crisis Needs at Scale: Using Natural Language Processing to Understand and Evaluate a Mental Health Crisis Text Messaging Service
Authors: Liu Zhaolu , Peach Robert L. , Lawrance Emma L. , Noble Ariele , Ungless Mark A. , Barahona Mauricio
Published: December 2021

The current mental health crisis is a growing public health issue requiring a large-scale response that cannot be met with traditional services alone. Digital support tools are proliferating, yet most are not systematically evaluated, and we know little about their users and their needs. Shout is a free mental health text messaging service run by the charity Mental Health Innovations, which provides support for individuals in the UK experiencing mental or emotional distress and seeking help. Here we study a large data set of anonymised text message conversations and post-conversation surveys compiled through Shout. This data provides an opportunity to hear at scale from those experiencing distress; to better understand mental health needs for people not using traditional mental health services; and to evaluate the impact of a novel form of crisis support. We use natural language processing (NLP) to assess the adherence of volunteers to conversation techniques and formats, and to gain insight into demographic user groups and their behavioural expressions of distress. Our textual analyses achieve accurate classification of conversation stages (weighted accuracy = 88%), behaviours (1-hamming loss = 95%) and texter demographics (weighted accuracy = 96%), exemplifying how the application of NLP to frontline mental health data sets can aid with post-hoc analysis and evaluation of quality of service provision in digital mental health services.
Seasonal Tidal Dynamics in the Qiantang Estuary: The Importance of Morphological Evolution
Authors: Xie Dongfeng , Wang Zheng Bing
Published: December 2021

Despite the increasing number of studies on the river-tide interactions in estuaries, less attention has been paid to the role of seasonal morphological changes on tidal regime. This study analyzes the seasonal interplay of river and tide in the Qiantang Estuary, China, particularly focusing on the influences of the active morphological evolution induced by the seasonal variation of river discharge. The study is based on the high and low water levels at three representative stations along the estuary and daily river discharge through 2015, an intermediate flow year in which a typical river flood occurred, as well as the bathymetric data measured in April, July and November, 2015. The results show strong seasonal variations of the water level in addition to the spring-neap variation. These variations are obviously due to the interaction between river discharge and tide but can only be fully explained by including the effect of morphological changes. Two types of the influences of the variation of the river discharge on the tidal dynamics in the estuary can be distinguished: one is immediately induced by the high flow and the other continues for a much longer period because of the bed erosion and the following bed recovery. Tidal range in the upper reach can be doubled after the flood because of bed erosion and then decrease under normal discharge periods due to sediment accumulation. Over a relatively short term such as a month or a spring-neap tidal cycle, there exist good relationships between the tidal range, tidal amplification in the upper reach and the tidal range at the mouth, and between the hydraulic head over the upper and lower reaches. Such relationships are unclear if all data over the whole year are considered together, mainly because of the active morphological evolution.
Assessing the Global and Local Uncertainty of Scientific Evidence in the Presence of Model Misspecification
Authors: Taper Mark L. , Lele Subhash R. , Ponciano José M. , Dennis Brian , Jerde Christopher L.
Published: December 2021

Scientists need to compare the support for models based on observed phenomena. The main goal of the evidential paradigm is to quantify the strength of evidence in the data for a reference model relative to an alternative model. This is done via an evidence function, such as ΔSIC, an estimator of the sample size scaled difference of divergences between the generating mechanism and the competing models. To use evidence, either for decision making or as a guide to the accumulation of knowledge, an understanding of the uncertainty in the evidence is needed. This uncertainty is well characterized by the standard statistical theory of estimation. Unfortunately, the standard theory breaks down if the models are misspecified, as is commonly the case in scientific studies. We develop non-parametric bootstrap methodologies for estimating the sampling distribution of the evidence estimator under model misspecification. This sampling distribution allows us to determine how secure we are in our evidential statement. We characterize this uncertainty in the strength of evidence with two different types of confidence intervals, which we term “global” and “local.” We discuss how evidence uncertainty can be used to improve scientific inference and illustrate this with a reanalysis of the model identification problem in a prominent landscape ecology study using structural equations.
Pleiotropic Loci Associated With Foot Disorders and Common Periparturient Diseases in Holstein Cattle
Authors: Lai Ellen , Danner Alexa L. , Famula Thomas R. , Oberbauer Anita M.
Published: December 2021

Lameness is an animal welfare issue that incurs substantial financial and environmental costs. This condition is commonly caused by digital dermatitis (DD), sole ulcers (SU), and white line disease (WLD). Susceptibility to these three foot disorders is due in part to genetics, indicating that genomic selection against these foot lesions can be used to reduce lameness prevalence. It is unclear whether selection against foot lesions will lead to increased susceptibility to other common diseases such as mastitis and metritis. Thus, the aim of this study was to determine the genetic correlation between causes of lameness and other common health disorders to identify loci contributing to the correlation. Genetic correlation estimates between SU and DD and between SU and WLD were significantly different from zero (p < 0.05), whereas estimates between DD and mastitis, DD and milk fever, and SU and metritis were suggestive (p < 0.1). All five of these genetic correlation estimates were positive. Two-trait genome-wide association studies (GWAS) for each of these five pairs of traits revealed common regions of association on BTA1 and BTA8 for pairs that included DD or SU as one of the traits, respectively. Other regions of association were unique to the pair of traits and not observed in GWAS for other pairs of traits. The positive genetic correlation estimates between foot disorders and other health disorders imply that selection against foot disorders may also decrease susceptibility to other health disorders. Linkage disequilibrium blocks defined around significant and suggestive SNPs from the two-trait GWAS included genes and QTL that were functionally relevant, supporting that these regions included pleiotropic loci.
Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis
Authors: Yang Kai , Xu Yi-Cheng , Hu Hua-Ying , Li Ya-Zhou , Li Qian , Luan Ying-Yi , Liu Yan , Sun Yong-Qing , Feng Zhan-Ke , Yan You-Sheng , Yin Cheng-Hong
Published: December 2021

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.

Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).

Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.

Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.
Identification of the Pyroptosis-Related Gene Signature and Risk Score Model for Colon Adenocarcinoma
Authors: Luo Bixian , Lin Jianwei , Cai Wei , Wang Mingliang
Published: December 2021

The prognosis of advanced colon adenocarcinoma (COAD) remains poor. However, existing methods are still difficult to assess patient prognosis. Pyroptosis, a lytic and inflammatory process of programmed cell death caused by the gasdermin protein, is involved in the development and progression of various tumors. Moreover, there are no related studies using pyroptosis-related genes to construct a model to predict the prognosis of COAD patients. Thus, in this study, bioinformatics methods were used to analyze the data of COAD patients downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to construct a risk model for the patient prognosis. TCGA database was used as the training set, and GSE39582 downloaded from GEO was used as the validation set. A total of 24 pyroptosis-related genes shown significantly different expression between normal and tumor tissues in COAD and seven genes (CASP4, CASP5, CASP9, IL6, NOD1, PJVK, and PRKACA) screened by univariate and LASSO cox regression analysis were used to construct the risk model. The receiver operating characteristic (ROC) and Kaplan–Meier (K–M curves) curves showed that the model based on pyroptosis-related genes can be used to predict the prognosis of COAD and can be validated by the external cohort well. Then, the clinicopathological factors were combined with the risk score to establish a nomogram with a C-index of 0.774. In addition, tissue validation results also showed that CASP4, CASP5, PRKACA, and NOD1 were differentially expressed between tumor and normal tissues from COAD patients. In conclusion, the risk model based on the pyroptosis-related gene can be used to assess the prognosis of COAD patients well, and the related genes may become the potential targets for treatment.
S-RNase Alleles Associated With Self-Compatibility in the Tomato Clade: Structure, Origins, and Expression Plasticity
Authors: Broz Amanda K. , Miller Christopher M. , Baek You Soon , Tovar-Méndez Alejandro , Acosta-Quezada Pablo Geovanny , Riofrío-Cuenca Tanya Elizabet , Rusch Douglas B. , Bedinger Patricia A.
Published: December 2021

The self-incompatibility (SI) system in the Solanaceae is comprised of cytotoxic pistil S-RNases which are countered by S-locus F-box (SLF) resistance factors found in pollen. Under this barrier-resistance architecture, mating system transitions from SI to self-compatibility (SC) typically result from loss-of-function mutations in genes encoding pistil SI factors such as S-RNase. However, the nature of these mutations is often not well characterized. Here we use a combination of S-RNase sequence analysis, transcript profiling, protein expression and reproductive phenotyping to better understand different mechanisms that result in loss of S-RNase function. Our analysis focuses on 12 S-RNase alleles identified in SC species and populations across the tomato clade. In six cases, the reason for gene dysfunction due to mutations is evident. The six other alleles potentially encode functional S-RNase proteins but are typically transcriptionally silenced. We identified three S-RNase alleles which are transcriptionally silenced under some conditions but actively expressed in others. In one case, expression of the S-RNase is associated with SI. In another case, S-RNase expression does not lead to SI, but instead confers a reproductive barrier against pollen tubes from other tomato species. In the third case, expression of S-RNase does not affect self, interspecific or inter-population reproductive barriers. Our results indicate that S-RNase expression is more dynamic than previously thought, and that changes in expression can impact different reproductive barriers within or between natural populations.
Characteristics of SP600125 Induced Tetraploid Cells in Comparison With Diploid and Tetraploid Cells of Fish
Authors: Fan Yunpeng , Zhang Guangjing , Zhao Kaiyue , Fu Wen , Chen Shujuan , Liu Jinhui , Liu Wenbin , Peng Liangyue , Ren Li , Liu Shaojun , Xiao Yamei
Published: December 2021

In our previous research, SP600125 (Anthrapyrazolone) was used to induce autotetraploid of crucian carp cells (SP4N cells), and tetraploid fry was generated from the SP4N cells by somatic cell nuclear transfer technique. However, it is still unclear about biological characteristics of the SP4N cells. In this article, the cytological characteristic and gene expression profiles of the SP4N cells are investigated in comparison with the crucian carp cells (2N cells) and the tetraploid crucian carp cells (CC4N cells). The SP4N cells have tetraploid characteristics in terms of morphology and DNA ploidy levels, and their chromosome behavior is stable during the cell proliferation. The migration ability and the mtDNA copy number of SP4N cells are both lower than those in the CC4N cells and the 2N cells, but there exist giant mitochondria in the SP4N cells. The similar expression trends in the cell cycle regulation genes of the SP4N cells and 2N cells, while the corresponding expression profiles are clearly different between the SP4N cells and the CC4N cells. Moreover, the significant difference genes are associated with energy metabolism pathways among the SP4N cells, 2N cells and CC4N cells. These results can provide deeper understanding of SP600125 induction, as well as finding applications in polyploidization breeding of fish species.
Rhesus Macaque CODEX Multiplexed Immunohistochemistry Panel for Studying Immune Responses During Ebola Infection
Authors: Jiang Sizun , Mukherjee Nilanjan , Bennett Richard S. , Chen Han , Logue James , Dighero-Kemp Bonnie , Kurtz Jonathan R. , Adams Ricky , Phillips Darci , Schürch Christian M. , Goltsev Yury , Hickey John W. , McCaffrey Erin F. , Delmastro Alea , Chu Pauline , Reader J. Rachel , Keesler Rebekah I. , Galván José A. , Zlobec Inti , Van Rompay Koen K. A. , Liu David X. , Hensley Lisa E. , Nolan Garry P. , McIlwain David R.
Published: December 2021

Non-human primate (NHP) animal models are an integral part of the drug research and development process. For some biothreat pathogens, animal model challenge studies may offer the only possibility to evaluate medical countermeasure efficacy. A thorough understanding of host immune responses in such NHP models is therefore vital. However, applying antibody-based immune characterization techniques to NHP models requires extensive reagent development for species compatibility. In the case of studies involving high consequence pathogens, further optimization for use of inactivated samples may be required. Here, we describe the first optimized CO-Detection by indEXing (CODEX) multiplexed tissue imaging antibody panel for deep profiling of spatially resolved single-cell immune responses in rhesus macaques. This 21-marker panel is composed of a set of 18 antibodies that stratify major immune cell types along with a set three Ebola virus (EBOV)-specific antibodies. We validated these two sets of markers using immunohistochemistry and CODEX in fully inactivated Formalin-Fixed Paraffin-Embedded (FFPE) tissues from mock and EBOV challenged macaques respectively and provide an efficient framework for orthogonal validation of multiple antibody clones using CODEX multiplexed tissue imaging. We also provide the antibody clones and oligonucleotide tag sequences as a valuable resource for other researchers to recreate this reagent set for future studies of tissue immune responses to EBOV infection and other diseases.
Aging-Related Impairments to M Cells in Peyer’s Patches Coincide With Disturbances to Paneth Cells
Authors: Donaldson David S. , Shih Barbara B. , Mabbott Neil A.
Published: December 2021

The decline in mucosal immunity during aging increases susceptibility, morbidity and mortality to infections acquired via the gastrointestinal and respiratory tracts in the elderly. We previously showed that this immunosenescence includes a reduction in the functional maturation of M cells in the follicle-associated epithelia (FAE) covering the Peyer’s patches, diminishing the ability to sample of antigens and pathogens from the gut lumen. Here, co-expression analysis of mRNA-seq data sets revealed a general down-regulation of most FAE- and M cell-related genes in Peyer’s patches from aged mice, including key transcription factors known to be essential for M cell differentiation. Conversely, expression of ACE2, the cellular receptor for SARS-Cov-2 virus, was increased in the aged FAE. This raises the possibility that the susceptibility of aged Peyer’s patches to infection with the SARS-Cov-2 virus is increased. Expression of key Paneth cell-related genes was also reduced in the ileum of aged mice, consistent with the adverse effects of aging on their function. However, the increased expression of these genes in the villous epithelium of aged mice suggested a disturbed distribution of Paneth cells in the aged intestine. Aging effects on Paneth cells negatively impact on the regenerative ability of the gut epithelium and could indirectly impede M cell differentiation. Thus, restoring Paneth cell function may represent a novel means to improve M cell differentiation in the aging intestine and increase mucosal vaccination efficacy in the elderly.
The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer—A Phase II Study
Authors: Xing Wenqun , Zhao Lingdi , Zheng Yan , Liu Baoxing , Liu Xianben , Li Tiepeng , Zhang Yong , Ma Baozhen , Yang Yonghao , Shang Yiman , Fu Xiaomin , Liang Guanghui , Yuan Dongfeng , Qu Jinrong , Chai Xiaofei , Zhang He , Wang Zibing , Lin Hongwei , Liu Liang , Ren Xiubao , Zhang Jiangong , Gao Quanli
Published: December 2021

Background

There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored.

Methods

This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival.

Results

Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery.

Conclusions

Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT 03985670.
Perspective of HLA-G Induced Immunosuppression in SARS-CoV-2 Infection
Authors: Lin Aifen , Yan Wei-Hua
Published: December 2021

COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened public health worldwide. Host antiviral immune responses are essential for viral clearance and disease control, however, remarkably decreased immune cell numbers and exhaustion of host cellular immune responses are commonly observed in patients with COVID-19. This is of concern as it is closely associated with disease severity and poor outcomes. Human leukocyte antigen-G (HLA-G) is a ligand for multiple immune inhibitory receptors, whose expression can be upregulated by viral infections. HLA-G/receptor signalling, such as engagement with immunoglobulin-like transcript 2 (ILT-2) or ILT-4, not only inhibit T and natural killer (NK) cell immune responses, dendritic cell (DC) maturation, and B cell antibody production. It also induces regulatory cells such as myeloid-derived suppressive cells (MDSCs), or M2 type macrophages. Moreover, HLA-G interaction with CD8 and killer inhibitory receptor (KIR) 2DL4 can provoke T cell apoptosis and NK cell senescence. In this context, HLA-G can induce profound immune suppression, which favours the escape of SARS-CoV-2 from immune attack. Although detailed knowledge on the clinical relevance of HLA-G in SARS-CoV-2 infection is limited, we herein review the immunopathological aspects of HLA-G/receptor signalling in SARS-CoV-2 infection, which could provide a better understanding of COVID-19 disease progression and identify potential immunointerventions to counteract SARS-CoV-2 infection.
The Identification and Prediction of Mesoscale Eddy Variation via Memory in Memory With Scheduled Sampling for Sea Level Anomaly
Authors: Nian Rui , Cai Yu , Zhang Zhengguang , He Hui , Wu Jingyu , Yuan Qiang , Geng Xue , Qian Yuqi , Yang Hua , He Bo
Published: December 2021

Ocean mesoscale eddies are ubiquitous in world ocean and account for 90% oceanic kinetic energy, which dominate the upper ocean flow field. Accurately predicting the variation of ocean mesoscale eddies is the key to understand the oceanic flow field and circulation system. In this article, we propose to make an initial attempt to explore spatio-temporal predictability of mesoscale eddies, employing deep learning architecture, which primarily establishes Memory In Memory (MIM) for sea level anomaly (SLA) prediction, combined with the existing mesoscale eddy detection. Oriented to the western Pacific ocean (125°−137.5°E and 15°−27.5°N), we quantitatively investigate the historic daily SLA variability at a 0.25° spatial resolution from 2000 to 2018, derived by satellite altimetry. We develop the enhanced MIM prediction strategies, equipped with Gated Recurrent Unit (GRU) and spatial attention module, in a scheduled sampling manner, which overcomes the gradient vanishing and complements to strengthen spatio-temporal features for long-term dependencies. At the early stage, the real value SLA input guides the model training process for initialization, while the scheduled sampling intentionally feeds the newly predicted value, to resolve the distribution inconsistency of inference. It has been demonstrated in our experiment results that our proposed prediction scheme outperformed the state-of-art approaches for SLA time series, with MAPE, RMSE of the 14-day prediction duration, respectively, 5.1%, 0.023 m on average, even up to 4.6%, 0.018 m for the effective sub-regions, compared to 19.8%, 0.086 m in ConvLSTM and 8.3%, 0.040 m in original MIM, which greatly facilitated the mesoscale eddy prediction. This proposed scheme will be beneficial to understand of the underlying dynamical mechanism behind the predictability of mesoscale eddies in the future, and help the deployment of ARGO, glider, AUV and other observational platforms.
Characterizing the Role of Glutamine synthetase Gene on Ammonia Nitrogen Detoxification Metabolism of the Razor Clam Sinonovacula constricta
Authors: Sun Gaigai , Sun Changsen , He Jing , Yao Hanhan , Dai Wenfang , Lin Zhihua , Dong Yinghui
Published: December 2021

Ammonia nitrogen is a common toxic substance in the aquatic system, which seriously threatens the survival and growth of clams. However, less is known about the ammonia metabolism and detoxification strategy in razor clam. In this study, the polymorphism of the Glutamine synthetase gene from Sinonovacula constricta (Sc-GS) was found to be related to ammonia tolerance. By comparing the coding sequence (CDS) region of Sc-GS from two geographical populations, a total of 14 and 12 single nucleotide polymorphisms (SNPs) were identified, respectively, of which 10 loci were shared between the two populations. Among them, the locus c.1133T > G exhibited an extremely significant and strong association with ammonia tolerance in both populations (P < 0.01), and it was missense mutation, which led to the amino acid change from leucine (Leu) to arginine (Arg). Furthermore, the results about H&E staining and immunohistochemistry of Sc-GS protein in gills and hepatopancreas revealed that it was specifically localized in the lateral cilia of gill filaments and the endothelial cells of hepatocytes. After inhibiting the Sc-GS expression by RNA interference (RNAi) technology, the transcript levels of Sc-GS were extremely significantly downregulated at 24, 48, 72, and 96 h (P < 0.01) in the hepatopancreas. Taken together, these results indicated that the Sc-GS gene may participate in ammonia metabolism. In addition, these results will help to demonstrate the role of Sc-GS in ammonia nitrogen metabolism and provide markers related to ammonia nitrogen tolerance for molecular marker-assisted selection (MAS) of the razor clam.
Tangshen Formula Improves Diabetes-Associated Myocardial Fibrosis by Inhibiting TGF-β/Smads and Wnt/β-Catenin Pathways
Authors: Hu Lin , Wang Yuyang , Wan Yuzhou , Ma Liang , Zhao Tingting , Li Ping
Published: December 2021

Cardiovascular disease has become the main cause of death among complications of diabetes. Myocardial fibrosis is a crucial pathological change of cardiovascular disease. Tangshen Formula (TSF) shows a good clinical effect in the treatment of diabetic kidney disease (DKD). However, whether TSF alleviates diabetes-associated myocardial fibrosis is still unknown. In the present research, we studied the effect and mechanism of TSF in the treatment of myocardial fibrosis in vivo and in vitro. We found that TSF treatment significantly downregulates myocardial fibrosis-related markers, including collagens I and III, and α-SMA. TSF also protects primary mouse cardiac fibroblast (CF) from transforming growth factor-β1- (TGF-β1-) induced damage. Moreover, TSF decreased the expression levels of TGF-β/Smad-related genes (α-SMA, collagens I and III, TGF-β1, and pSmad2/3), and increased Smad7 gene expression. Finally, TSF decreased the expressions of wnt1, active-β-catenin, FN, and MMP7 to regulate the Wnt/β-catenin pathway. Taken together, TSF seems to attenuate myocardial fibrosis in KKAy mice by inhibiting TGF-β/Smad2/3 and Wnt/β-catenin signaling pathways.
Dysnatremias in Chronic Kidney Disease: Pathophysiology, Manifestations, and Treatment
Authors: Arzhan Soraya , Lew Susie Q. , Ing Todd S. , Tzamaloukas Antonios H. , Unruh Mark L.
Published: December 2021

The decreased ability of the kidney to regulate water and monovalent cation excretion predisposes patients with chronic kidney disease (CKD) to dysnatremias. In this report, we describe the clinical associations and methods of management of dysnatremias in this patient population by reviewing publications on hyponatremia and hypernatremia in patients with CKD not on dialysis, and those on maintenance hemodialysis or peritoneal dialysis. The prevalence of both hyponatremia and hypernatremia has been reported to be higher in patients with CKD than in the general population. Certain features of the studies analyzed, such as variation in the cut-off values of serum sodium concentration ([Na]) that define hyponatremia or hypernatremia, create comparison difficulties. Dysnatremias in patients with CKD are associated with adverse clinical conditions and mortality. Currently, investigation and treatment of dysnatremias in patients with CKD should follow clinical judgment and the guidelines for the general population. Whether azotemia allows different rates of correction of [Na] in patients with hyponatremic CKD and the methodology and outcomes of treatment of dysnatremias by renal replacement methods require further investigation. In conclusion, dysnatremias occur frequently and are associated with various comorbidities and mortality in patients with CKD. Knowledge gaps in their treatment and prevention call for further studies.
Exosomes From Human Urine-Derived Stem Cells Encapsulated Into PLGA Nanoparticles for Therapy in Mice With Particulate Polyethylene-Induced Osteolysis
Authors: Li Hui , Hu Yihe , Zeng Min , Yang Junxiao , Fan Xiaolei , Wang Yinan , Xie Jie
Published: December 2021

Background: Periprosthetic osteolysis is the primary reason for arthroplasty failure after total joint replacement because of the generation of wear particles and subsequent bone erosion around the prosthesis, which leads to aseptic loosening. Periprosthetic osteolysis is often treated with revision surgery because of the lack of effective therapeutic agents. As key messengers of intercellular interactions, exosomes can be independently used as therapeutic agents to promote tissue repair and regeneration. In this study, we fabricated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that carry exosomes derived from human urine stem cells (USC-Exos) and explored their effects on polyethylene-induced osteolysis.

Methods: USCs were identified by multipotent differentiation and flow cytometry analyses. USC-Exos were isolated and identified by transmission electron microscopy (TEM), dynamic light scattering (DLS), and western blotting. PLGA microspheres containing USC-Exos were fabricated to synthesize NPs using the mechanical double-emulsion method. The obtained NPs were characterized in terms of stability, toxicity, exosome release, and cell uptake. Then, these NPs were implanted into the murine air pouch model, and their effects on polyethylene-induced osteolysis were evaluated by microcomputed tomography (micro-CT) and histological analyses.

Results: The average NP diameter was ~282 ± 0.4 nm, and the zeta potential was −2.02 ± 0.03 mV. After long-term storage at room temperature and 4°C, the NP solution was stable without significant coaggregation. In vitro release profiles indicated sustained release of exosomes for 12 days. In vivo, injection of NPs into the murine air pouch caused less osteolysis than that of USC-Exos, and NPs significantly reduced bone absorption, as indicated by histology and micro-CT scanning.

Conclusion: Our findings suggest that USC-Exo-based PLGA NPs can prevent particulate polyethylene-induced osteolysis and bone loss.
NTF3 Correlates With Prognosis and Immune Infiltration in Hepatocellular Carcinoma
Authors: Liu Rongqiang , Li Rongqi , Yu Haoyuan , Liu Jianrong , Zheng Shiyang , Li Yang , Ye Linsen
Published: December 2021

Background: The potential role of Neurotrophic factor-3(NTF3) in liver cancer is unknown. Therefore, we aimed to explore the clinical value of NTF3 in hepatocellular carcinoma (HCC).

Methods: We used a variety of databases to analyze the expression, relationship with prognosis and immune significance of NTF3 in liver cancer through bioinformatics.

Results: NTF3 was low expressed in HCC and was an independent prognostic factor in patients with HCC. CIBERSORT analysis indicated that NTF3 expression was positively correlated with CD4+ cells, mast cells, NK cells, macrophages and B cells in the tumor microenvironment. Furthermore, we found that NTF3 expression was negatively correlated with the immune checkpoints PD-L1, TIGIT and TIM-3. Functional network analysis revealed that NTF3 regulates HCC progression through a variety of cancer-related kinases, transcription factors and signaling pathways.

Conclusions: We demonstrate that NTF3 correlates with prognosis and immune infiltration in HCC.
Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia
Authors: Welekidan Letemichael Negash , Yimer Solomon Abebe , Skjerve Eystein , Dejene Tsehaye Asmelash , Homberset Håvard , Tønjum Tone , Brynildsrud Ola
Published: December 2021

Background: Tuberculosis, mainly caused by Mycobacterium tuberculosis (Mtb), is an ancient human disease that gravely affects millions of people annually. We wanted to explore the genetic diversity and lineage-specific association of Mtb with drug resistance among pulmonary tuberculosis patients.

Methods: Sputum samples were collected from pulmonary tuberculosis patients at six different healthcare institutions in Tigray, Ethiopia, between July 2018 and August 2019. DNA was extracted from 74 Mtb complex isolates for whole-genome sequencing (WGS). All genomes were typed and screened for mutations with known associations with antimicrobial resistance using in silico methods, and results were cross-verified with wet lab methods.

Results: Lineage (L) 4 (55.8%) was predominant, followed by L3 (41.2%); L1 (1.5%) and L2 (1.5%) occurred rarely. The most frequently detected sublineage was CAS (38.2%), followed by Ural (29.4%), and Haarlem (11.8%). The recent transmission index (RTI) was relatively low. L4 and Ural strains were more resistant than the other strains to any anti-TB drug (P < 0.05). The most frequent mutations to RIF, INH, EMB, SM, PZA, ETH, FLQs, and 2nd-line injectable drugs occurred at rpoB S450L, katG S315T, embB M306I/V, rpsL K43R, pncA V139A, ethA M1R, gyrA D94G, and rrs A1401G, respectively. Disputed rpoB mutations were also shown in four (16%) of RIF-resistant isolates.

Conclusion: Our WGS analysis revealed the presence of diverse Mtb genotypes. The presence of a significant proportion of disputed rpoB mutations highlighted the need to establish a WGS facility at the regional level to monitor drug-resistant mutations. This will help control the transmission of DR-TB and ultimately contribute to the attainment of 100% DST coverage for TB patients as per the End TB strategy.
Dihedral Angle Measurements for Structure Determination by Biomolecular Solid-State NMR Spectroscopy
Authors: van der Wel Patrick C. A.
Published: December 2021

In structural studies of immobilized, aggregated and self-assembled biomolecules, solid-state NMR (ssNMR) spectroscopy can provide valuable high-resolution structural information. Among the structural restraints provided by magic angle spinning (MAS) ssNMR the canonical focus is on inter-atomic distance measurements. In the current review, we examine the utility of ssNMR measurements of angular constraints, as a complement to distance-based structure determination. The focus is on direct measurements of angular restraints via the judicious recoupling of multiple anisotropic ssNMR parameters, such as dipolar couplings and chemical shift anisotropies. Recent applications are highlighted, with a focus on studies of nanocrystalline polypeptides, aggregated peptides and proteins, receptor-substrate interactions, and small molecule interactions with amyloid protein fibrils. The review also examines considerations of when and where ssNMR torsion angle experiments are (most) effective, and discusses challenges and opportunities for future applications.
Lower Cognitive Set Shifting Ability Is Associated With Stiffer Balance Recovery Behavior and Larger Perturbation-Evoked Cortical Responses in Older Adults
Authors: Payne Aiden M. , Palmer Jacqueline A. , McKay J. Lucas , Ting Lena H.
Published: December 2021

The mechanisms underlying associations between cognitive set shifting impairments and balance dysfunction are unclear. Cognitive set shifting refers to the ability to flexibly adjust behavior to changes in task rules or contexts, which could be involved in flexibly adjusting balance recovery behavior to different contexts, such as the direction the body is falling. Prior studies found associations between cognitive set shifting impairments and severe balance dysfunction in populations experiencing frequent falls. The objective of this study was to test whether cognitive set shifting ability is expressed in successful balance recovery behavior in older adults with high clinical balance ability (N = 19, 71 ± 7 years, 6 female). We measured cognitive set shifting ability using the Trail Making Test and clinical balance ability using the miniBESTest. For most participants, cognitive set shifting performance (Trail Making Test B-A = 37 ± 20 s) was faster than normative averages (46 s for comparable age and education levels), and balance ability scores (miniBESTest = 25 ± 2/28) were above the threshold for fall risk (23 for people between 70 and 80 years). Reactive balance recovery in response to support-surface translations in anterior and posterior directions was assessed in terms of body motion, muscle activity, and brain activity. Across participants, lower cognitive set shifting ability was associated with smaller peak center of mass displacement during balance recovery, lower directional specificity of late phase balance-correcting muscle activity (i.e., greater antagonist muscle activity 200–300 ms after perturbation onset), and larger cortical N1 responses (100–200 ms). None of these measures were associated with clinical balance ability. Our results suggest that cognitive set shifting ability is expressed in balance recovery behavior even in the absence of profound clinical balance disability. Specifically, our results suggest that lower flexibility in cognitive task performance is associated with lower ability to incorporate the directional context into the cortically mediated later phase of the motor response. The resulting antagonist activity and stiffer balance behavior may help explain associations between cognitive set shifting impairments and frequent falls.
Templating Functional Materials Using Self-Assembled Block Copolymer Thin-Film for Nanodevices
Authors: Subramanian Ashwanth , Tiwale Nikhil , Lee Won-Il , Nam Chang-Yong
Published: December 2021

The nanomorphologies and nanoarchitectures that can be synthesized using block copolymer (BCP) thin-film self-assembly have inspired a variety of new applications, which offer various advantages, such as, small device footprint, low operational power and enhanced device performance. Imperative for these applications, however, is the ability to transform these small polymeric patterns into useful inorganic structures. BCP-templated inorganic nanostructures have shown the potential for use as active materials in various electronic device applications, including, field-effect transistors, photodetectors, gas sensors and many more. This article reviews various strategies that have been implemented in the past decade to fabricate devices at nanoscale using block copolymer thin films.