bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice
Authors: Ogawa Yuko , Okinaka Yuka , Takeuchi Yukiko , Saino Orie , Kikuchi-Taura Akie , Taguchi Akihiko
Published: November 2020

There is no effective treatment for chronic stroke if the acute or subacute phase is missed. Rehabilitation alone cannot easily achieve a dramatic recovery in function. In contrast to significant therapeutic effects of bone marrow mononuclear cells (BM-MNC) transplantation for acute stroke, mild and non-significant effects have been shown for chronic stroke. In this study, we have evaluated the effect of a combination of BM-MNC transplantation and neurological function training in chronic stroke. The effect of BM-MNC on neurological functional was tested four weeks after permanent middle cerebral artery occlusion (MCAO) insult in mice. BM-MNC (1 × 105cells in 100 μl PBS) were injected into the vein of MCAO model mice, followed by behavioral tests as functional evaluations. Interestingly, there was a significant therapeutic effect of BM-MNC only when repeated training was performed. This suggested that cell therapy alone was not sufficient for chronic stroke treatment; however, training with cell therapy was effective. The combination of these differently targeted therapies provided a significant benefit in the chronic stroke mouse model. Therefore, targeted cell therapy via BM-MNC transplantation with appropriate training presents a promising novel therapeutic option for patients in the chronic stroke period.
Stream Microbial Community Structured by Trace Elements, Headwater Dispersal, and Large Reservoirs in Sub-Alpine and Urban Ecosystems
Authors: Jones Erin Fleming , Griffin Natasha , Kelso Julia E. , Carling Gregory T. , Baker Michelle A. , Aanderud Zachary T.
Published: November 2020

Stream bacterioplankton communities, a crucial component of aquatic ecosystems and surface water quality, are shaped by environmental selection (i.e., changes in taxa abundance associated with more or less favorable abiotic conditions) and passive dispersal (i.e., organisms’ abundance and distribution is a function of the movement of the water). These processes are a function of hydrologic conditions such as residence time and water chemistry, which are mediated by human infrastructure. To quantify the role of environmental conditions, dispersal, and human infrastructure (dams) on stream bacterioplankton, we measured bacterioplankton community composition in rivers from sub-alpine to urban environments in three watersheds (Utah, United States) across three seasons. Of the 53 environmental parameters measured (including physicochemical parameters, solute concentrations, and catchment characteristics), trace element concentrations explained the most variability in bacterioplankton community composition using Redundancy Analysis ordination. Trace elements may correlate with bacterioplankton due to the commonality in source of water and microorganisms, and/or environmental selection creating more or less favorable conditions for bacteria. Bacterioplankton community diversity decreased downstream along parts of the stream continuum but was disrupted where large reservoirs increased water residence time by orders of magnitude, potentially indicating a shift in the relative importance of environmental selection and dispersal at these sites. Reservoirs also had substantial effects on community composition, dissimilarity (Bray-Curtis distance) and species interactions as indicated by co-occurrence networks. Communities downstream of reservoirs were enriched with anaerobic Sporichthyaceae, methanotrophic Methylococcaceae, and iron-transforming Acidimicrobiales, suggesting alternative metabolic pathways became active in the hypolimnion of large reservoirs. Our results identify that human activity affects river microbial communities, with potential impacts on water quality through modified biogeochemical cycling.
The Microbiota Dynamics of Alfalfa Silage During Ensiling and After Air Exposure, and the Metabolomics After Air Exposure Are Affected by Lactobacillus casei and Cellulase Addition
Authors: Hu Zongfu , Niu Huaxin , Tong Qing , Chang Jie , Yu Jianhua , Li Shuguo , Zhang Shi , Ma Deying
Published: November 2020

Both inoculants treatment and enzyme treatment promote the reproduction of lactic acid bacteria (LAB) to produce enough lactic acid to lower pH in silage. The present study investigated the microbial community and metabolome in cellulase, Lactobacillus casei, and air treated alfalfa silage. Chopped and wilted alfalfa (first cutting, 29% dry matter) was ensiled without (CON) or with L. casei (1 × 106 cfu g–1 fresh matter) (LC) or cellulase (20,000IU, 0.5% of fresh matter) (CE) for 56 days, then exposed to air for 3 days (PO). Greater ensiling quality was observed in LC and CE, which had lower pH and higher lactic acid content than CON at 56 days of ensiling and 3 days post-oxygen exposure. Air exposure was associated with decreased lactic acid concentrations and increased yeast and mold counts in all silages. SEM showed that the structure of leaf epicuticular wax crystals were intact in fresh alfalfa, totally decomposed in CON silage, and partly preserved in CE and LC silage. Gas chromatography mass spectrometry revealed that 196 metabolites and 95 differential concentration were present in the 3 days air exposure samples. Most of these metabolites, mainly organic acids, polyols, ketones, aldehydes, are capable of antimicrobial activity. The bacterial communities were obviously different among groups and Lactobacillus developed to a dominant status in all silages. Lactobacillus became dominant in bacterial communities of LC and CE silages from days 7 to 56, and their relative abundances reached 94.17–83.93% at day 56, respectively. For CON silage, until day 56, Lactobacillus dominated the bacterial community with abundance of 75.10%. After 3 days of oxygen exposure, Lactobacillus and Enterococcus were predominant in CON, and Lactobacillus remained dominant in LC and CE silages. The results indicated that, compared to untreated silages, L. casei could be a priority inoculant for alfalfa silage to boost Lactobacillus abundance and improve fermentation quality. Our high-throughput sequencing and gas chromatography mass spectrometry results provide a deep insight into the bacterial community and metabolites in alfalfa silage.
Orally Administered Antibiotics Vancomycin and Ampicillin Cause Cognitive Impairment With Gut Dysbiosis in Mice With Transient Global Forebrain Ischemia
Authors: Lee Kyung-Eon , Kim Jeon-Kyung , Kim Dong-Hyun
Published: November 2020

Gut microbiota is closely associated with the occurrence of neuropsychiatric disorders. Antibiotics are frequently used to prevent pathogen infection in patients with brain ischemia. To understand the impact of prophylactic antibiotic treatment for patients with brain ischemia, we examined the effects of orally administered vancomycin and ampicillin on cognitive function and gut microbiota composition in mice with transient global forebrain ischemia (tIsc). tIsc operation and orally gavaged vancomycin mildly and moderately caused cognitive impairment, respectively. However, the exposure of mice with tIsc to vancomycin or ampicillin severely impaired cognitive function in the Y-maze, novel object recognition, and Banes maze tasks. Furthermore, their treatments induced NF-κB activation as well as active microglia (NF-κB+/Iba1+ and LPS+/Iba1+ cells) and apoptotic (caspase 3+/NeuN+) cell population in the hippocampus, whereas the brain-derived neurotrophic factor (BDNF)+/NeuN+ cell populations decreased. These treatments also caused colitis and gut dysbiosis. They increased the population of Proteobacteria including Enterobacter xiangfangenesis. Orally delivered fecal transplantation of vancomycin-treated mice with or without tIsc and oral gavage of Enterobacter xiangfangenesis also significantly deteriorated the cognitive impairment and colitis in transplanted mice with tIsc. These findings suggest that oral administration of antibiotics can deteriorate cognitive impairment with gut dysbiosis in patients with brain ischemia.
Increasing Yield of 2,3,5,6-Tetramethylpyrazine in Baijiu Through Saccharomyces cerevisiae Metabolic Engineering
Authors: Cui Dan-Yao , Wei Ya-Nan , Lin Liang-Cai , Chen Shi-Jia , Feng Peng-Peng , Xiao Dong-Guang , Lin Xue , Zhang Cui-Ying
Published: November 2020

Baijiu is a traditional distilled beverage in China with a rich variety of aroma substances. 2,3,5,6-tetramethylpyrazine (TTMP) is an important component in Baijiu and has the function of promoting cardiovascular and cerebrovascular health. During the brewing of Baijiu, the microorganisms in jiuqu produce acetoin and then synthesize TTMP, but the yield of TTMP is very low. In this work, 2,3-butanediol dehydrogenase (BDH) coding gene BDH1 and another BDH2 gene were deleted or overexpressed to evaluate the effect on the content of acetoin and TTMP in Saccharomyces cerevisiae. The results showed that the acetoin synthesis of strain α5-D1B2 was significantly enhanced by disrupting BDH1 and overexpressing BDH2, leading to a 2.6-fold increase of TTMP production up to 10.55 mg/L. To further improve the production level of TTMP, the α-acetolactate synthase (ALS) of the pyruvate decomposition pathway was overexpressed to enhance the synthesis of diacetyl. However, replacing the promoter of the ILV2 gene with a strong promoter (PGK1p) to increase the expression level of the ILV2 gene did not result in further increased diacetyl, acetoin and TTMP production. Based on these evidences, we constructed the diploid strains AY-SB1 (ΔBDH1:loxP/ΔBDH1:loxP) and AY-SD1B2 (ΔBDH1:loxP-PGK1p-BDH2-PGK1t/ΔBDH1:loxP-PGK1p-BDH2-PGK1t) to ensure the fermentation performance of the strain is more stable in Baijiu brewing. The concentration of TTMP in AY-SB1 and AY-SD1B2 was 7.58 and 9.47 mg/L, respectively, which represented a 2.3- and 2.87-fold increase compared to the parental strain. This work provides an example for increasing TTMP production in S. cerevisiae by genetic engineering, and highlight a novel method to improve the quality and beneficial health attributes of Baijiu.
Osteoblast and Osteoclast Activity Affect Bone Remodeling Upon Regulation by Mechanical Loading-Induced Leukemia Inhibitory Factor Expression in Osteocytes
Authors: Du Jingke , Yang Jiancheng , He Zihao , Cui Junqi , Yang Yiqi , Xu Mingming , Qu Xinhua , Zhao Ning , Yan Mengning , Li Hanjun , Yu Zhifeng
Published: November 2020

Purpose

Bone remodeling is affected by mechanical stimulation. Osteocytes are the primary mechanical load-sensing cells in the bone, and can regulate osteoblast and osteoclast activity, thus playing a key role in bone remodeling. Further, bone mass during exercise is also regulated by Leukemia inhibitory factor (LIF). This study aimed to investigate the role of LIF in the mechanical response of the bone,in vivoandin vitro, and to elucidate the mechanism by which osteocytes secrete LIF to regulate osteoblasts and osteoclasts.

Methods

A tail-suspension (TS) mouse model was used in this study to mimic muscular disuse. ELISA and immunohistochemistry were performed to detect bone and serum LIF levels. Micro-computed tomography (CT) of the mouse femurs was performed to measure three-dimensional bone structure parameters. Fluid shear stress (FSS) and microgravity simulation experiments were performed to study mechanical stress-induced LIF secretion and its resultant effects. Bone marrow macrophages (BMMs) and bone mesenchymal stem cells (BMSCs) were cultured to inducein vitroosteoclastogenesis and osteogenesis, respectively.

Results

Micro-CT results showed that TS mice exhibited deteriorated bone microstructure and lower serum LIF expression. LIF secretion by osteocytes was promoted by FSS and was repressed in a microgravity environment. Further experiments showed that LIF could elevate the tartrate-resistant acid phosphatase activity in BMM-derived osteoclasts through the STAT3 signaling pathway. LIF also enhanced alkaline phosphatase staining and osteogenesis-related gene expression during the osteogenic differentiation of BMSCs.

Conclusion

Mechanical loading affected LIF expression levels in osteocytes, thereby altering the balance between osteoclastogenesis and osteogenesis.
Acupuncture Therapy for Cognitive Impairment: A Delphi Expert Consensus Survey
Authors: Su Xin-Tong , Wang Li-Qiong , Li Jin-Ling , Zhang Na , Wang Lu , Shi Guang-Xia , Yang Jing-Wen , Liu Cun-Zhi
Published: November 2020

Background

Current research evidence challenges clinical decision-making when acupuncture is taken into consideration in the treatment of cognitive impairment (CI). Aiming to provide some viable recommendations for acupuncture practitioners in dealing with actual clinic issues, an expert consensus study was conducted.

Methods

A clinical question investigation among 47 acupuncturists yielded 24 initial items. Subsequently, systematic reviews on acupuncture for CI were searched within three online databases. A panel of 30 authoritative experts were requested to respond with agreement, neutrality, or disagreement for each item. Consensus establishment was defined as the percentage of agreement on a given item >80%.

Results

Following a 2-round Delphi survey, there were 21 items reaching consensus and three items resulting in no consensus; of which 10 items reached 90∼100% agreement, and 80∼90% expert agreement was achieved for 11 items. These items could be roughly categorized into six domains: (1) therapeutic effects of acupuncture, (2) therapeutic principles, (3) acupoint selection and combination, (4) acupuncture parameters, (5) considerable combined therapies, and (6) possible adverse events.

Conclusion

Without ready-made guidelines, this expert consensus may be conducive to guide acupuncturists in implementing clinical acupuncture practice for CI. Moreover, given the lack of high-quality research evidence and plenty of unresolved clinical issues in this field, it is of necessity to carry out more studies to better clarify the treatment algorithm.
Analysis of Interictal Epileptiform Discharges in Mesial Temporal Lobe Epilepsy Using Quantitative EEG and Neuroimaging
Authors: Fujisao Elaine Keiko , Alves Karen Fernanda , Rezende Thais O. P. , Betting Luiz Eduardo
Published: November 2020

Objective: Investigate areas of correlation between gray matter volumes by MRI and interictal EEG source maps in subtypes of mesial temporal lobe epilepsy (MTLE).

Method: 71 patients and 36 controls underwent 3T MRI and and routine EEG was performed. Voxel-based morphometry (VBM) was used for gray matter analysis and analysis of interictal discharge sources for quantitative EEG. Voxel-wise correlation analysis was conducted between the gray matter and EEG source maps in MTLE subtypes.

Results: The claustrum was the main structure involved in the individual source analysis. Twelve patients had bilateral HA, VBM showed bilateral hippocampal. Twenty-one patients had right HA, VBM showed right hippocampal and thalamic atrophy and negatively correlated involving the right inferior frontal gyrus and insula. Twenty-two patients had left HA, VBM showed left hippocampal atrophy and negatively correlated involving the left temporal lobe and insula. Sixteen patients had MTLE without HA, VBM showed middle cingulate gyrus atrophy and were negatively correlated involving extra-temporal regions, the main one located in postcentral gyrus.

Conclusions: Negative correlations between gray matter volumes and EEG source imaging. Neuroanatomical generators of interictal discharges are heterogeneous and vary according to MTLE subtype.

Significance: These findings suggest different pathophysiological mechanisms among patients with different subtypes of MTLE.
Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis
Authors: Verhoog Quirijn P. , Holtman Linda , Aronica Eleonora , van Vliet Erwin A.
Published: November 2020

Astrocytes are key homeostatic regulators in the central nervous system and play important roles in physiology. After brain damage caused by e.g., status epilepticus, traumatic brain injury, or stroke, astrocytes may adopt a reactive phenotype. This process of reactive astrogliosis is important to restore brain homeostasis. However, persistent reactive astrogliosis can be detrimental for the brain and contributes to the development of epilepsy. In this review, we will focus on physiological functions of astrocytes in the normal brain as well as pathophysiological functions in the epileptogenic brain, with a focus on acquired epilepsy. We will discuss the role of astrocyte-related processes in epileptogenesis, including reactive astrogliosis, disturbances in energy supply and metabolism, gliotransmission, and extracellular ion concentrations, as well as blood-brain barrier dysfunction and dysregulation of blood flow. Since dysfunction of astrocytes can contribute to epilepsy, we will also discuss their role as potential targets for new therapeutic strategies.
Continuous Visual Focal Status Epilepticus as the Primary Presentation of NMDA-R and GAD65-R Autoimmune Epilepsy
Authors: Paredes-Aragón Elma M. , Valdéz-Ruvalcaba Héctor E. , Santos-Peyret Andrea , Cisneros-Otero Marcela , Medina-Rioja Raúl , Orozco-Suárez Sandra , Hernandez Miriam M. , Breda-Yepes Michele D. L. , Rivas-Alonso Verónica , Flores-Rivera José J. , Martínez-Juárez Iris E.
Published: November 2020

Epilepsia partialis continua (EPC) has changed in its clinical and pathophysiological definition throughout time. Several etiologies have been described in addition to classic causes of EPC. The following case depicts a young woman who had a peculiar onset of epilepsy with a continuous visual aura becoming a form of chronic recurrent and non-progressive EPC. The patient was initially misdiagnosed as a non-neurological entity (assumed psychiatric in origin), but finally, an immune-mediated epilepsy was diagnosed, and EEG showed focal status epilepticus during evolution. Once the diagnosis was achieved and immune treatment was established, the patient is seizure free. Early identification of an immune basis in patients with epilepsy is important because immunotherapy can reverse the epileptogenic process and reduce the risk of chronic epilepsy. To date, this is the only case reported with EPC manifesting as a continuous visual aura associated with antiglutamic acid decarboxylase 65 (anti-GAD65) and anti-N-methyl-d-aspartate (anti-NMDA) antibodies.
Factors Influencing Saccadic Reaction Time: Effect of Task Modality, Stimulus Saliency, Spatial Congruency of Stimuli, and Pupil Size
Authors: Yamagishi Shimpei , Furukawa Shigeto
Published: November 2020

It is often assumed that the reaction time of a saccade toward visual and/or auditory stimuli reflects the sensitivities of our oculomotor-orienting system to stimulus saliency. Endogenous factors, as well as stimulus-related factors, would also affect the saccadic reaction time (SRT). However, it was not clear how these factors interact and to what extent visual and auditory-targeting saccades are accounted for by common mechanisms. The present study examined the effect of, and the interaction between, stimulus saliency and audiovisual spatial congruency on the SRT for visual- and for auditory-target conditions. We also analyzed pre-target pupil size to examine the relationship between saccade preparation and pupil size. Pupil size is considered to reflect arousal states coupling with locus-coeruleus (LC) activity during a cognitive task. The main findings were that (1) the pattern of the examined effects on the SRT varied between visual- and auditory-auditory target conditions, (2) the effect of stimulus saliency was significant for the visual-target condition, but not significant for the auditory-target condition, (3) Pupil velocity, not absolute pupil size, was sensitive to task set (i.e., visual-targeting saccade vs. auditory-targeting saccade), and (4) there was a significant correlation between the pre-saccade absolute pupil size and the SRTs for the visual-target condition but not for the auditory-target condition. The discrepancy between target modalities for the effect of pupil velocity and between the absolute pupil size and pupil velocity for the correlation with SRT may imply that the pupil effect for the visual-target condition was caused by a modality-specific link between pupil size modulation and the SC rather than by the LC-NE (locus coeruleus-norepinephrine) system. These results support the idea that different threshold mechanisms in the SC may be involved in the initiation of saccades toward visual and auditory targets.
Zero Echo Time MRAC on FDG-PET/MR Maintains Diagnostic Accuracy for Alzheimer’s Disease; A Simulation Study Combining ADNI-Data
Authors: Ando Takahiro , Kemp Bradley , Warnock Geoffrey , Sekine Tetsuro , Kaushik Sandeep , Wiesinger Florian , Delso Gaspar
Published: November 2020

Aim

Attenuation correction using zero-echo time (ZTE) – magnetic resonance imaging (MRI) (ZTE-MRAC) has become one of the standard methods for brain-positron emission tomography (PET) on commercial PET/MR scanners. Although the accuracy of the net tracer-uptake quantification based on ZTE-MRAC has been validated, that of the diagnosis for dementia has not yet been clarified, especially in terms of automated statistical analysis. The aim of this study was to clarify the impact of ZTE-MRAC on the diagnosis of Alzheimer’s disease (AD) by performing simulation study.

Methods

We recruited 27 subjects, who underwent both PET/computed tomography (CT) and PET/MR (GE SIGNA) examinations. Additionally, we extracted 107 subjects from the Alzheimer Disease Neuroimaging Initiative (ADNI) dataset. From the PET raw data acquired on PET/MR, three FDG-PET series were generated, using two vendor-provided MRAC methods (ZTE and Atlas) and CT-based AC. Following spatial normalization to Montreal Neurological Institute (MNI) space, we calculated each patient’s specific error maps, which correspond to the difference between the PET image corrected using the CTAC method and the PET images corrected using the MRAC methods. To simulate PET maps as if ADNI data had been corrected using MRAC methods, we multiplied each of these 27 error maps with each of the 107 ADNI cases in MNI space. To evaluate the probability of AD in each resulting image, we calculated a cumulative t-value using a fully automated method which had been validated not only in the original ADNI dataset but several multi-center studies. In the method, PET score = 1 is the 95% prediction limit of AD. PET score and diagnostic accuracy for the discrimination of AD were evaluated in simulated images using the original ADNI dataset as reference.

Results

Positron emission tomography score was slightly underestimated both in ZTE and Atlas group compared with reference CTAC (−0.0796 ± 0.0938 vs. −0.0784 ± 0.1724). The absolute error of PET score was lower in ZTE than Atlas group (0.098 ± 0.075 vs. 0.145 ± 0.122, p < 0.001). A higher correlation to the original PET score was observed in ZTE vs. Atlas group (R2: 0.982 vs. 0.961). The accuracy for the discrimination of AD patients from normal control was maintained in ZTE and Atlas compared to CTAC (ZTE vs. Atlas. vs. original; 82.5% vs. 82.1% vs. 83.2% (CI 81.8–84.5%), respectively).

Conclusion

For FDG-PET images on PET/MR, attenuation correction using ZTE-MRI had superior accuracy to an atlas-based method in classification for dementia. ZTE maintains the diagnostic accuracy for AD.
A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade
Authors: Granzotto Alberto , Canzoniero Lorella M. T. , Sensi Stefano L.
Published: November 2020

Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.
Early Loss of Fat Mass During Chemoradiotherapy Predicts Overall Survival in Locally Advanced Squamous Cell Carcinoma of the Lung, but Not in Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Willemsen A. C. H. , Degens J. H. R. J. , Baijens L. W. J. , Dingemans A-M. C. , Hoeben A. , Hoebers F. J. P. , De Ruysscher D. K. M. , Schols A. M. W. J.
Published: November 2020

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV–) LAHNSCC patients treated with CRT.

Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent.

Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13–2.39], p = 0.01 and HR 2.30 [95%CI 1.33–3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC (n = 64) [HR 3.80 [95%CI 1.79–8.06] p ≤ 0.001] but not in HPV– LAHNSCC (n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV– LAHNSCC n = 23), the FM change was −1.4 ± 14.5% and −8.7 ± 9.0% in sNSCLC and HPV– LAHNSCC patients, respectively (p < 0.05). Fat fee mass change was −5.6 ± 6.3% and −4.0 ± 4.3% for sNSCLC and HPV– LAHNSCC, respectively (p = 0.31).

Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV– LAHNSCC patients. Early FM loss was prognostic in sNSCLC only.
Upregulated Collagen COL10A1 Remodels the Extracellular Matrix and Promotes Malignant Progression in Lung Adenocarcinoma
Authors: Liang Yingkuan , Xia Wenjie , Zhang Te , Chen Bing , Wang Hui , Song Xuming , Zhang Zeyu , Xu Lin , Dong Gaochao , Jiang Feng
Published: November 2020

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.
Sintilimab: A Promising Anti-Tumor PD-1 Antibody
Authors: Zhang Lin , Mai Wuqian , Jiang Wenyang , Geng Qing
Published: November 2020

Sintilimab (Tyvyt®) is a monoclonal antibody against programmed cell death protein 1 (PD-1). It could block the interaction between PD-1 and its ligands and help the anti-tumor effect of T-cells to recover. Sintilimab is developed by Innovent Biologics and Eli Lilly and Company and has been approved to treat relapsed or refractory classical Hodgkin lymphoma in patients who have undergone two or more lines of systemic chemotherapy by the National Medical Products Administration of China. Recently, sintilimab has been reported in plenty of literature and shows satisfying anti-tumor effect. Meanwhile, there are some reports showing its side effects. Overall, sintilimab has similar anti-tumor effects and a better safety profile compared to nivolumab and pembrolizumab in Hodgkin lymphoma, natural killer/T cell lymphoma and advanced non-small cell lung cancer. In this review, we aim to briefly describe the mechanisms, pharmacological characteristics, anti-tumor effects, predictive parameters of efficacy and side effects of sintilimab, providing valuable information of sintilimab for decision-making in the treatment of tumors in the future.
Deciphering the Pharmacological Mechanisms of Ma Xing Shi Gan Decoction against COVID-19 through Integrating Network Pharmacology and Experimental Exploration
Authors: Li Qianqian , Bai Chen , Yang Ruocong , Xing Weiying , Pang Xiaohan , Wu Siying , Liu Shaoyang , Chen Jianxin , Liu Tiegang , Gu Xiaohong
Published: November 2020

The outbreak of new infectious pneumonia caused by SARS-CoV-2 has posed a significant threat to public health, but specific medicines and vaccines are still being developed. Traditional Chinese medicine (TCM) has thousands of years of experience in facing the epidemic disease, such as influenza and viral pneumonia. In this study, we revealed the efficacy and pharmacological mechanism of Ma Xing Shi Gan (MXSG) Decoction against COVID-19. First, we used liquid chromatography–electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) to analyze the chemical components in MXSG and identified a total of 97 components from MXSG. Then, the intervention pathway of MXSG based on these components was analyzed with network pharmacology, and it was found that the pathways related to the virus infection process were enriched in some of MXSG component targets. Simultaneously, through literature research, it was preliminarily determined that MXSG, which is an essential prescription for treating COVID-19, shared the feature of antiviral, improving clinical symptoms, regulating immune inflammation, and inhibiting lung injury. The regulatory mechanisms associated with its treatment of COVID-19 were proposed. That MXSG might directly inhibit the adsorption and replication of SARS-CoV-2 at the viral entry step. Besides, MXSG might play a critical role in inflammation and immune regulatory, that is, to prevent cytokine storm and relieve lung injury through toll-like receptors signaling pathway. Next, in this study, the regulatory effect of MXSG on inflammatory lung injury was validated through transcriptome results. In summary, MXSG is a relatively active and safe treatment for influenza and viral pneumonia, and its therapeutic effect may be attributed to its antiviral and anti-inflammatory effects.
The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress
Authors: Yin Yong-Yu , Tian Chao-Yang , Fang Xin-Xin , Shang Chao , Zhang Li-Ming , Xu Qiang , Li Yun-Feng
Published: November 2020

Given the limited monkey models of depression available to date, as well as the procedural complexity and time investments that they involve, the ability to test the efficacy and time course of antidepressants in monkey models is greatly restricted. The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT1A receptor partial agonist and 5-HT6 receptor full agonist. Female cynomolgus monkeys with low social status in their colonies were selected and subjected to CUS for 8 weeks by means of food and water deprivation, space restriction, loud noise, strobe light, and intimidation with fake snakes. Huddling, self-clasping, locomotion and environmental exploration were monitored to evaluate behavioral changes. In addition, the window-opening test was used to evaluate the exploratory interest of the monkeys. The present results revealed that CUS-exposed monkeys displayed significant depression-like behaviors, including significant decreases in exploratory interest, locomotion, and exploration as well as significant increases in huddling and self-clasping behavior and the level of fecal cortisol after 8 weeks of CUS. Treatment with FLX (2.4 mg/kg, i. g.) or YL-0919 (1.2 mg/kg, i. g.) markedly reversed the depression-like behaviors caused by CUS, producing significant antidepressant effects. YL-0919 (once daily for 9 days) had a faster-onset antidepressant effect, compared with FLX (once daily for 17 days). In summary, the present study first established a CUS model using female cynomolgus monkeys with low social status and then successfully evaluated the onset time of 5-HTergic antidepressants. The results suggested that monkeys exposed to CUS displayed significant depression-like behaviors, and both FLX and YL-0919 produced antidepressant effects in this model. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model.
Breather Structures and Peregrine Solitons in a Polarized Space Dusty Plasma
Authors: Singh Kuldeep , Saini N. S.
Published: November 2020

In this theoretical investigation, we have examined the combined effects of nonthermally revamped polarization force on modulational instability MI of dust acoustic waves DAWs and evolution of different kinds of dust acoustic (DA) breathers in a dusty plasma consisting of negatively charged dust as fluid, Maxwellian electrons, and ions obeying Cairns’ nonthermal distribution. The nonthermality of ions has considerably altered the strength of polarization force. By employing the multiple-scale perturbation technique, the nonlinear Schrödinger equation NLSE is derived to study modulational MI instability of dust acoustic waves DAWs. It is noticed that influence of the polarization force makes the wave number domain narrow where MI sets in. The rational solutions of nonlinear Schrödinger equation illustrate the evolution of DA breathers, namely, Akhmediev breather, Kuznetsov–Ma breather, and Peregrine solitons (rogue waves). Further, the formation of super rogue waves due to nonlinear superposition of DA triplets rogue waves is also discussed. It is analyzed that combined effects of variation in the polarization force and nonthermality of ions have a comprehensive influence on the evolution of different kinds of DA breathers. It is remarked that outcome of present theoretical investigation may provide physical insight into understanding the role of nonlinear phenomena for the generation of various types of DA breathers in experiments and different regions of space (e.g., the planetary spoke and cometary tails).
Intermittent Hypoxia Mediates Caveolae Disassembly That Parallels Insulin Resistance Development
Authors: Varela-Guruceaga Maider , Belaidi Elise , Lebeau Lucie , Aka Ella , Andriantsitohaina Ramaroson , Giorgetti-Peraldi Sophie , Arnaud Claire , Le Lay Soazig
Published: November 2020

Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients.
Pax9’s Interaction With the Ectodysplasin Signaling Pathway During the Patterning of Dentition
Authors: Jia Shihai , Oliver Jeremie D. , Turner Emma C. , Renouard Maranda , Bei Marianna , Wright J. T. , D’Souza Rena N.
Published: November 2020

In these studies, we explored for the first time the molecular relationship between the paired-domain-containing transcription factor,Pax9, and the ectodysplasin (Eda) signaling pathway during mouse incisor formation. Mice that were deficient in bothPax9andEdawere generated, and the status of dentition analyzed in all progeny using gross evaluation and histomorphometric means. When compared to wildtype controls,Pax9+/–Eda–/–mice lack mandibular incisors. Interestingly,FgfandShhsignaling are down-regulated whileBmp4andLef1appear unaffected. These findings suggest thatPax9-dependent signaling involves theEdapathway and that this genetic relationship is important for mandibular incisor development. Studies of records of humans affected by mutations inPAX9lead to the congenital absence of posterior dentition but interestingly involve agenesis of mandibular central incisors. The latter phenotype is exhibited by individuals withEDAorEDARmutations. Thus, it is likely thatPAX9, in addition to playing a role in the formation of more complex dentition, is also involved withEDAsignaling in the initiation of odontogenesis within the incisal domain.
Phosphorylation and Circadian Molecular Timing
Authors: Brenna Andrea , Albrecht Urs
Published: November 2020

Endogenous circadian rhythms are biological processes generated by an internal body clock. They are self-sustaining, and they govern biochemical and physiological processes. However, circadian rhythms are influenced by many external stimuli to reprogram the phase in response to environmental change. Through their adaptability to environmental changes, they synchronize physiological responses to environmental challenges that occur within a sidereal day. The precision of this circadian system is assured by many post-translational modifications (PTMs) that occur on the protein components of the circadian clock mechanism. The most ancient example of circadian rhythmicity driven by phosphorylation of clock proteins was observed in cyanobacteria. The influence of phosphorylation on the circadian system is observed through different kingdoms, from plants to humans. Here, we discuss how phosphorylation modulates the mammalian circadian clock, and we give a detailed overview of the most critical discoveries in the field.
A Micropropagation Protocol for the Endangered Medicinal Tree Prunus africana (Hook f.) Kalkman: Genetic Fidelity and Physiological Parameter Assessment
Authors: Komakech Richard , Kim Yong-Goo , Kim Wook Jin , Omujal Francis , Yang Sungyu , Moon Byeong Cheol , Okello Denis , Rahmat Endang , Kyeyune Grace Nambatya , Matsabisa Motlalepula Gilbert , Kang Youngmin
Published: November 2020

Prunus africana is an endangered medicinal plant and hence new propagation methods are urgently required to increase its populations. Unfortunately, propagation through seeds is challenging due to its long flowering cycle and recalcitrant seeds. We developed a protocol for micropropagation using nodal segment explants. A woody plant medium supplemented with vitamins, 15 g L−1 sucrose, and 1.0 mg L−1 6-benzylaminopurine (BAP) supported the optimum rate (100%) of axillary shoot initiation. Supplementation with 15 g L−1 sucrose and 1.5 mg L−1 indole-3-acetic acid (IAA) provided the optimum rate (75%) of root initiation. Rooted plantlets were successfully planted in sterilized horticultural soil containing perlite (2:1 v/v) and the survival rate was 98% following acclimatization. The photosynthetic rate assessed using FlourPen FP110 series showed that the ratio of variable fluorescence to maximum fluorescence mean value for in vitro regenerated P. africana (0.830 ± 0.0008) was similar to that of the maternal P. africana plant (0.825 ± 0.005), indicating similarity in their photosynthetic performance; a pivotal process for growth and development. The Fourier transform near-IR (FT-NIR) spectrometer analysis of the in vitro regenerated and the maternal P. africana plant samples exhibited homogeneity in the absorbance peaks at 8,273, 6,344, and 4,938–4,500 cm−1 associated with lipids, starch, and proteins. The genetic fidelity of regenerated plants was confirmed using the randomly amplified polymorphic DNA (RAPD) technique. Our protocol is suitable for use in large-scale P. africana to meet the increasing demands for it in the global market.
Behavioral Immune System Responses to Coronavirus: A Reinforcement Sensitivity Theory Explanation of Conformity, Warmth Toward Others and Attitudes Toward Lockdown
Authors: Bacon Alison M. , Corr Philip J.
Published: November 2020

Behavioral immune system (BIS) describes psychological mechanisms that detect cues to infectious pathogens in the immediate environment, trigger disease-relevant responses and facilitate behavioral avoidance/escape. BIS activation elicits a perceived vulnerability to disease (PVD) which can result in conformity with social norms. However, a response to superficial cues can result in aversive responses to people that pose no actual threat, leading to an aversion to unfamiliar others, and likelihood of prejudice. Pathogen-neutralizing behaviors, therefore, have implications for social interaction as well as illness behaviors and responses to health communications. In this study, we investigate how PVD influences conformity, attitudes to other people and to lockdown regulations through the lens of the Reinforcement Sensitivity Theory (RST). RST describes personality in terms of biologically-driven approach and avoidance motivations which support personal goals. Participants from the United Kingdom public (N = 605) completed an RST personality questionnaire and then read either (a) coronavirus morbidity-mortality statistics and current United Kingdom government lifestyle regulations, (b) just the regulations (as presented in most government publicity materials), or (c) no information at all. They all completed the Perceived Vulnerability to Disease scale to assess BIS-relevant Germ Aversion and Perceived Infectability, followed by questions measuring social conformity, warmth toward others and attitudes toward lockdown measures. Significantly lower PVD scores were observed in the no-information condition, with the other conditions showing no difference. In terms of RST, approach behaviors related to goal-drive persistence work alongside fear in explaining conformity to social norms. Reward related approach behaviors partially explained warmth toward others, indicating that social rewards gained through interaction continue to be strong drivers of behavior. We found no role for RST traits in attitudes toward lockdown. Overall, coronavirus-related behavior is not driven purely by fear, but also by social and/or protection goals regulated by approach motivation. This study presents new insights into public perceptions of coronavirus and government regulated lifestyle restrictions, helping to explain social behaviors in terms of biologically driven mechanisms. Such understanding is vital if we are to successfully motivate public behavior to constrain spread of the virus.