bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of excision repair cross complementation group 1 rs2298881 in patients with gastric cancer receiving platinum-based chemotherapy
Authors: Lv Yalei , Xu Mengyuan , Sun Yidan , Liu Yezhou , Zhao Lijuan , Liu Xuehui , Li Zixuan , Shi Gaiping , Jia Jinhai , Bi Lanfei , Ma Ning , Zhang Xiaolin , Qi Cheng
Published: August 2021

Background:

Gastric cancer (GC) is a strong cause of global cancer mortality. Nucleotide excision repair (NER) can modulate platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. Some studies have found a link between excision repair cross complementation group 1 (ERCC1) rs2298881, one gene in NER pathway, and response to chemotherapy. However, the results have been disputed.

Methods:

We conducted a meta-analysis to reevaluate the association between polymorphisms of NER gene (ERCC1 rs2298881) and the clinical outcomes in gastric cancer patients receiving platinum-based chemotherapy. Searching PubMed, Web of Science, EMBASE, Google Scholar, and China National Knowledge Infrastructure, 2 independent searchers found all pertinent literatures up to May 1, 2021. We enrolled studies according to consistent selection criteria, extracted and vitrified data. Crude odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were applied to evaluate the effect of ERCC1 rs2298881 on patients treated by platinum-based chemotherapy.

Results:

By the data gathered from 6 independent studies, 1940 cases diagnosed with gastric cancer and treated with chemotherapy were included, containing 1208 Good-Responders and 732 Poor-Responders. With a comprehensive meta-analysis, we found that the patients with ERCC1 rs2298881A allele had a worse response to chemotherapy than those who with rs2298881C allele under allelic model (A vs C), with the pooled OR of 0.780 (95% CI: 0.611–0.996, P = .046). And our analysis indicated that AA genotype was associated with unfavorable overall survival (HR = 1.540, 95% CI = 1.106–2.144, P = .011) compared with CC genotype.

Conclusions:

ERCC1 rs2298881 is suggested as a marker of clinical outcome in gastric cancer patients treated by platinum-based chemotherapy.
Relationship between end-tidal carbon dioxide and arterial carbon dioxide in critically ill patients on mechanical ventilation
Authors: Wang Jinrong , Zhang Jianjun , Liu Yajing , Shang Huimian , Peng Li , Cui Zhaobo
Published: August 2021

So far, only a few studies have examined and confirmed the correlation between end-expiratory carbon dioxide partial pressure (PETCO2) and arterial carbon dioxide tension (PaCO2) during invasive mechanical ventilation in critically ill patients. This study aimed to observe the correlation between PaCO2 and PETCO2 in patients on invasive mechanical ventilation.

This was a cross-sectional study of adult patients on invasive mechanical ventilation enrolled between June 2018 and March 2019. Patients requiring invasive mechanical ventilation underwent one of the following mechanical ventilation modes: assisted/controlled ventilation, synchronized intermittent mandatory ventilation, and spontaneous breathing. Subsequently, the difference and correlation between PETCO2 and PaCO2 were analyzed.

A total of 184 patients with 298 pairs of PETCO2-PaCO2 data were included in the analysis. Without distinguishing the ventilator mode, there was significant positive correlation between PETCO2 and PaCO2. In different ventilator modes, the correlation coefficient was 0.81 for synchronized intermittent mandatory ventilation, 0.47 for assisted/controlled ventilation, and 0.55 for spontaneous breathing, respectively. In patients with chronic obstructive pulmonary disease (r = 0.80), multiple trauma (r = 0.64), severe pneumonia (r = 0.60), gastrointestinal surgery (r = 0.57), and cerebrovascular diseases (r = 0.53), PETCO2 and PaCO2 were positively correlated. For oxygenation index <200 mm Hg, correlation coefficient r = 0.69, P < .001; oxygenation index ≥200, r = 0.73, P < .001. Under different oxygenation indexes, there was no statistically significant difference between the 2 correlation coefficients. Among 116 pairs of data with oxygenation index <200 mm Hg, the difference of PaCO2-PETCO2 ≥10 mm Hg was found in 25 pairs (21.55%); in 182 pairs of data with oxygenation index ≥200 mm Hg, the difference of PaCO2-PETCO2 ≥10 mm Hg was found in 26 pairs

In patients on invasive mechanical ventilation, there was a good correlation between PETCO2 and PaCO2 in different ventilator modes, different disease types, and different oxygenation indexes, especially in synchronized intermittent mandatory ventilation mode and chronic obstructive pulmonary disease patients.
Pulmonary hypertension in patients with chronic myeloid leukemia
Authors: Song Ik-Chan , Yeon Sang-Hoon , Lee Myeong-Won , Ryu Hyewon , Lee Hyo-Jin , Yun Hwan-Jung , Sun Byung Joo , Park Jae-Hyeong , Jeong Jin-Ok , Jo Deog-Yeon
Published: August 2021

Dasatinib, a tyrosine kinase inhibitor (TKI), induces pulmonary hypertension (PH) in patients with chronic myeloid leukemia (CML). However, information on other TKIs is limited.

We retrospectively analyzed PH prevalence by reviewing transthoracic echocardiography (TTE) findings in a population of Korean CML patients treated with TKI at a single hospital between 2003 and 2020. PH was defined as a high PH probability according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.

Of the 189 patients treated with TKI(s) during the study period, 112 (59.3%) underwent TTE. Among the 112 patients treated with a TKI for a median of 40.4 months (range: 1.1–167.2 months), PH was found in 12 (10.7%), most frequently in those treated with dasatinib (ie, in 3 [7.5%] of 40 of those treated with imatinib, 1 [3.1%] of 32 of those treated with nilotinib, and 8 [21.6%] of 37 of those treated with dasatinib). PH resolved in 4 (50.0%) of the 8 dasatinib-treated patients after discontinuation of the agent. One nilotinib-treated and all three imatinib-treated patients recovered from PH. In multivariate analyses, age >60 years, dasatinib treatment, and positive cardiopulmonary symptoms/signs at the time of transthoracic echocardiography were statistically significant risk factors for developing PH.

These results show that PH is induced not only by dasatinib, but also by imatinib and nilotinib. Careful screening for PH during any TKI treatment may thus be warranted in patients with CML.
Comparison of 10 noninvasive models for predicting overall survival in patients with intermediate-stage hepatocellular carcinoma
Authors: Hsu Wei-Fan , Chang Kai-Chih , Chen Te-Hong , Lin Chien-Hung , Lin Ying-Chun , Tsai Ming-Hung , Chen Pei-Yu , Wang Hung-Wei , Chu Chia-Sheng , Peng Cheng-Yuan
Published: August 2021

Intermediate-stage hepatocellular carcinoma (HCC) is heterogeneous in terms of tumor size, number, and effects on liver function. Various noninvasive models have been proposed to assess functional hepatic reserve or fibrosis severity in patients with HCC. This study assessed the feasibility of 10 noninvasive models and compared their prognostic ability for patients with intermediate-stage HCC.

This study retrospectively enrolled 493 patients with intermediate-stage HCC who received treatment at China Medical University Hospital from January 2012 to November 2018. Demographic data, clinical features, and factors associated with overall survival (OS) were recorded at baseline. Receiver-operating characteristic curve analysis and the DeLong method were respectively employed to evaluate and compare the models’ OS prediction performance.

Of the 493 patients, 373 (75.7%) were male, and 275 (55.8%) had liver cirrhosis (LC). The median age was 64 years (interquartile range: 55–72). Most patients had tumor volume ≤50% (n = 424, 86.0%), and the maximum tumor size was 6.0 (4.0–8.5) cm. The median α-fetoprotein was 36.25 (6.13–552.91) ng/mL. The patients underwent transarterial chemoembolization (TACE, n = 349) or surgery (n = 144). The median follow-up period was 26.07 (9.77–48.27) months. Across the 10 models, the albumin–bilirubin (ALBI) score had the highest area under the receiver operating characteristic curve (AUROC) (0.644, 95% confidence interval: 0.595–0.693) in all patients. In subgroup analyses, the Lok index, platelet–albumin–bilirubin score, ALBI score, and Lok index had the highest AUROC values in patients without cirrhosis, with cirrhosis, undergoing TACE, and undergoing surgery, respectively. Multivariate Cox regression analysis revealed that independent predictors of longer OS were ALBI grade 1 in all patients, patients with LC, and patients undergoing TACE and Lok index grade 1 in patients without LC and patients undergoing surgery.

Among the 10 noninvasive models, ALBI score exhibited the highest diagnostic value in predicting OS for all patients, patients with cirrhosis, and those undergoing TACE, and Lok index grade exhibited the highest diagnostic value in predicting OS in patients without cirrhosis and those undergoing surgery.
Comparison of functional dorsal attention network alterations in breast cancer survivors before and after chemotherapy
Authors: Shen Chao-Yu , Tsai Yuan-Hsiung , Chen Vincent Chin-Hung , Chou Ming-Chih , McIntyre Roger S. , Weng Jun-Cheng
Published: August 2021

Breast cancer is the leading type of cancer among women worldwide, and a high number of breast cancer patients are suffering from psychological and cognitive disorders. This cross-sectional study used resting-state functional magnetic resonance imaging (rs-fMRI) and clinical neuropsychological tests to evaluate the possible underlying mechanisms.

We enrolled 32 breast cancer patients without chemotherapy (BC), 32 breast cancer patients within 6 to 12 months after the completion of chemotherapy (BC_CTx) and 46 healthy controls. Participants underwent neuropsychological tests and rs-fMRI with mean fractional amplitude of low-frequency fluctuation and mean regional homogeneity analyses. Between groups whole-brain voxel-wise rs-fMRI comparisons were calculated using two-sample t test. rs-fMRI and neuropsychological tests correlation analyses were calculated using multiple regression. Age and years of education were used as covariates. A false discovery rate-corrected P-value of less than .05 was considered statistically significant.

We found significantly alteration of mean fractional amplitude of low-frequency fluctuation and mean regional homogeneity in the frontoparietal lobe and occipital lobe in the BC group compared with the other 2 groups, indicating alteration of functional dorsal attention network (DAN). Furthermore, we found the DAN alteration was correlated with neuropsychological impairment.

The majority of potential underlying mechanisms of DAN alteration in BC patients may due to insufficient frontoparietal lobe neural activity to drive DAN and may be related to the effects of neuropsychological distress. Further longitudinal studies with comprehensive images and neuropsychological tests correlations are recommended.
Treatment outcomes of induction chemotherapy combined with intensity-modulated radiotherapy and adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma in Southeast China
Authors: Wang Peirong , Dong Feng , Cai Chuanshu , Ke Chunlin
Published: August 2021

Induction chemotherapy (IC) and adjuvant chemotherapy (AC) are used to enhance tumor locoregional control and support early treatment for distant metastases. However, optimum combinatorial treatment of these chemoradiotherapy regimens with radiotherapy in curing locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. Here, we evaluate the efficacy and therapeutic outcome of a combinatorial treatment strategy involving IC, intensity-modulated radiotherapy (IMRT), and AC, by retrospectively analyzing 243 NPC patients who were treated by IC followed by IMRT and AC. The rates of 3-/5-year local-regional control rate, distant failure-free rate (DFFR), progression-free survival (PFS), and overall survival (OS) were 93.3%/90.3%, 84.2%/79.4%, 79.6%/74.4%, and 84.0%/72.6%, respectively. The 3-/5-year OS rates of patients in stage III or IVA were 91.5%/75.1% and 86.5%/56.5%, respectively. Combination cisplatin with paclitaxel showed no significance in OS as compared to cisplatin plus 5-fluorouracil (P-value = .17). Total four-cycle IC and AC was significantly beneficious versus three-cycle in DFFR (P-value = .04), as well as total 6 chemotherapy cycles compared to 4 in DFFR and PFS (P-value = .03 and P-value = .01, respectively). All survival indicators were adversely affected by T-category, while N-category could only predict DFFR and PFS. Radiation dosage represented as a second prognostic factor for local control. We propose that IC combined with IMRT and AC for locoregionally advanced NPC shows effective treatment outcomes.
Adenosquamous Carcinoma With Ductal Differentiation of the Tongue
Authors: Felicelli Christopher , Ananthanarayanan Vijayalakshmi , Mudaliar Kumaran
Published: August 2021

Carcinomas of the tongue with ductal differentiation are rare entities and provide a diagnostic conundrum. We present a case of a patient with a tongue mass that showed a highly invasive tumor with glandular and squamoid features, as well as with ductal differentiation, most compatible with an adenosquamous carcinoma (AdSC) with ductal differentiation, which has not previously been described. The differential diagnosis of the lesion is discussed and a review of the literature regarding AdSC is undertaken.
Tertiary Syphilis Involving the Larynx: A Rare Case Report
Authors: Thakkar Bhushan , Carlisle Wesley D. , Redfield Samantha , Meram Andrew T.
Published: August 2021

Syphilis is one of the most common sexually transmitted diseases. In recent years, a resurgence of syphilis has been described in the literature, with a 71.4% increase in documented cases in the United States from 2014 to 2018. Tertiary syphilis remains rare in developed countries. We report a case of tertiary laryngeal syphilis in a middle-aged man presenting with cervical lymphadenopathy and an oropharyngeal mass with clinical features suggestive of malignancy. Precise pathologic examination with laboratory testing revealed the final diagnosis. We review the imaging and pathologic findings to emphasize the importance of taking syphilis into consideration in the differential diagnosis of oropharyngeal masses.
Mechanical Insufflation Exsufflation, Syringomyelia, and Headache
Authors: Bach John R. , Purewal Anam
Published: August 2021

Mechanical insufflation exsufflation creates cough flows to clear central airways secretions for patients with ineffective cough flows. At times, patients with even potentially effective spontaneous cough flows can have pain that prevents effective coughing. We describe a patient with Arnold-Chiari syndrome, syringomyelia, and hydrocephalus who had nine episodes of pneumonia through the age of 9 yrs, and cough associated headaches, who upon using mechanical insufflation exsufflation had no subsequent pneumonias for at least the next 17 yrs and no headaches when using it for coughing.
Genomic profiles of vaccine breakthrough SARS-CoV-2 strains from Odisha, India
Authors: Ghosh Arup , Walia Safal , Rattan Roma , Kanampalliwar Amol , Jha Atimukta , Aggarwal Shifu , Fatma Sana , Das Niyati , Chayani Nirupama , Prasad Punit , Raghav Sunil K. , Parida Ajay
Published: August 2021

Vaccine breakthrough infections pose a vast challenge in the eradication of the COVID pandemic situation. Emerging SARS-CoV-2 variants of concern infecting the immunized individuals indicate an ongoing battle between host immunity and natural selection of the pathogen. Our report sheds light on the prominent SARS-CoV-2 variations observed in the isolates from AZD1222/Covishield and BBV152/Covaxin vaccinated subjects.
Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains
Authors: Elvers Karen T. , Lipka-Lloyd Magdalena , Trueman Rebecca C. , Bax Benjamin D. , Mehellou Youcef
Published: August 2021

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and Oxidative Stress Responsive 1 (OSR1) kinase are two serine/threonine protein kinase that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream With No Lysine Kinases (WNKs), facilitating their activation via phosphorylation. Thus, the inhibition of SPAK and OSR1 binding, via their CCT domains, to WNK kinases is a plausible strategy for inhibiting SPAK and OSR1 kinases. To facilitate structure-guided drug design of such inhibitors, we expressed and purified human SPAK and OSR1 CCT domains and solved their crystal structures. We also employed a biophysical strategy and determined the affinity of SPAK and OSR1 CCT domains to an 18-mer peptide derived from WNK4. Together, the crystal structures and affinity data reported herein provide a robust platform to facilitate the design of CCT domain specific small molecule inhibitors of SPAK-activation by WNK kinases, potentially leading to new improved treatments for hypertension and ischemic stroke.
ITRAQ-based quantitative proteomic analysis of japonica rice seedling during cold stress
Authors: Qing Dongjin , Pan Yinghua , Dai Gaoxing , Gao Lijun , Liang Haifu , Zhou Weiyong , Chen Weiwei , Li Jingcheng , Huang Juan , Gao Ju , Lu Chunju , Wu Hao , Liu Kaiqiang , Deng Guofu
Published: August 2021

Low temperature is one of the important environmental factors that affect rice growth and yield. To better understand the japonica rice responses to cold stress, isobaric tags for relative and absolute quantification (iTRAQ) labeling based quantitative proteomics approach was used to detected changes in protein level. Two-week-old seedlings of the cold tolerance rice variety Kongyu131 were treated at 8°C for 24, 48 and 72 h, then the total proteins were extracted from tissues and used for quantitative proteomics analysis. A total of 5082 proteins were detected for quantitative analysis, of which 289 proteins were significantly regulated, consisting of 169 uniquely up-regulated proteins and 125 uniquely down-regulated proteins in cold stress groups relative to control group. Functional analysis revealed most of regulation proteins involved in photosynthesis, metabolic pathway, biosynthesis of secondary metabolites and carbon metabolism. Western blot analysis showed that protein regulation was consistent with the iTRAQ data. The corresponding genes of 25 regulation proteins were used for quantitative real time PCR analysis, and the results showed that the mRNA level was not always parallel to the corresponding protein level. The importance of our study is providing new insights into cold stress responses in rice on proteomic aspect.
DPPA2 and DPPA4 are dispensable for mouse zygotic genome activation and preimplantation development
Authors: Chen Zhiyuan , Xie Zhenfei , Zhang Yi
Published: August 2021

How maternal factors in oocytes initiate zygotic genome activation (ZGA) remains elusive. Recent studies indicate that DPPA2 and DPPA4 are required for establishing a 2-cell embryo-like (2C-like) state in mouse embryonic stem cells (ESCs) in a DUX-dependent manner. These results suggest that DPPA2 and DPPA4 are essential maternal factors that regulate Dux and ZGA in embryos. By analyzing maternal knockout and maternal-zygotic knockout embryos, we unexpectedly found that Dux activation, ZGA, and preimplantation development are normal in embryos without DPPA2 or DPPA4. Thus, unlike in ESCs/2C-like cells, DPPA2 and DPPA4 are dispensable for ZGA and preimplantation development.
Probing the Structure and Functional Properties of the Dropout-induced Correlated Variability in Convolutional Neural Networks
Authors: Pan Xu , Coen-Cagli Ruben , Schwartz Odelia
Published: August 2021

Computational neuroscience studies have shown that the structure of neural variability to an unchanged stimulus affects the amount of information encoded. Some artificial deep neural networks, e.g. those with Monte Carlo dropout layers, also have variable responses when the input is fixed. However, the structure of the trial-by-trial neural co-variance in neural networks with dropout has not been studied and its role in decoding accuracy is unknown. We studied the above questions in a convolutional neural network model with dropout in both the training and testing phase. We found that trial-by-trial correlation between neurons, i.e. noise correlation, is positive and low-dimensional. Neurons that are close in a feature map have larger noise correlation. These properties are surprisingly similar to the findings in the visual cortex. We further analyzed the alignment of the main axes of the covariance matrix. We found that different images share a common trial-by-trial noise covariance subspace, and they are aligned with the global signal covariance. The above evidence that the noise covariance is aligned with signal covariance suggests that noise covariance in dropout neural networks reduces network accuracy, which we further verified directly with a trial-shuffling procedure commonly used in neuroscience. These findings highlight a previously overlooked as-pect of dropout layers that can affect network performance. Such dropout networks could also potentially be a computational model of neural variability.
Covalent inhibition of endoplasmic reticulum chaperone GRP78 disconnects the transduction of ER stress signals to inflammation and lipid accumulation in diet-induced obese mice
Authors: Luo Dan , Fan Ni , Zhang Xiuying , Ngo Fung Yin , Zhao Jia , Zhao Wei , Huang Min , Li Ding , Wang Yu , Rong Jianhui
Published: August 2021

Targeting endoplasmic reticulum (ER) stress, inflammation and metabolic dysfunctions may halt the pathogenesis of obesity and thereby reduce the prevalence of diabetes, cardiovascular disesases and cancers. The present study was designed to elucidate the mechnaisms by which plant-derived celastrol ameliorated inflammation and lipid accumulation in obesity. The mouse model of diet-induced obesity was induced by feeding high-fat diet for 3 months and subsequently intervented with celastrol for 21 days. Hepatic and adipose tissues were analysed for lipid accumulation, macrophage activation and biomarker expression. As result, celastrol effectively reduced body weight, suppressed ER stress, inflammation and lipogenesis while promoted hepatic lipolysis. RNA-sequencing revealed that celastrol-loaded nanomicelles restored the expression of 49 genes that regulate ER stress, inflammation and lipid metabolism. On the other hand, celastrol-PEG4-alkyne was synthesized for identifying celastrol-bound proteins in RAW264.7 macrophages. ER chaperone GRP78 was identified by proteomics approach for celastrol binding to the residue Cys41. Upon binding and conjugation, celastrol diminished the chaperone activity of GRP78 by 130-fold and reduced ER stress in palmitate-challenged cells, while celastrol analogue lacking quinone methide failed to exhibit anti-obesity effects. Thus, covalent GRP78 inhibition may induce the reprograming of ER signaling, inflammation and metabolism against diet-induced obesity.
Microscale concert hall acoustics to produce uniform ultrasound stimulation for targeted sonogenetics in hsTRPA1-transfected cells
Authors: Vasan Aditya , Allein Florian , Duque Marc , Magaram Uri , Boechler Nicholas , Chalasani Sreekanth H. , Friend James
Published: August 2021

The field of ultrasound neuromodulation has rapidly developed over the past decade, a consequence of the discovery of strain-sensitive structures in the membrane and organelles of cells extending into the brain, heart, and other organs. Notably, clinical trials are underway for treating epilepsy using focused ultrasound to elicit an organized local electrical response. A key limitation to this approach is the formation of standing waves within the skull. In standing acoustic waves, the maximum ultrasound intensity spatially varies from near zero to double the mean in one half a wavelength, and can lead to localized tissue damage and disruption of normal brain function while attempting to evoke a broader response. This phenomenon also produces a large spatial variation in the actual ultrasound exposure in tissue, leading to heterogeneous results and challenges with interpreting these effects. One approach to overcome this limitation is presented herein: transducer-mounted diffusers that result in spatiotemporally incoherent ultrasound. The signal is numerically and experimentally quantified in an enclosed domain with and without the diffuser. Specifically, we show that adding the diffuser leads to a two-fold increase in ultrasound responsiveness of hsTRPA1 transfected HEK cells. Furthermore, we demonstrate the diffuser allow us to produce an uniform spatial distribution of pressure in the rodent skull. Collectively, we propose that our approach leads to a means to deliver uniform ultrasound into irregular cavities for sonogenetics.
Diversification of small RNA pathways underlies germline RNAi incompetence in wild C. elegans strains
Authors: Chou Han Ting , Valencia Francisco , Alexander Jacqueline C. , Bell Avery Davis , Deb Diptodip , Pollard Daniel A. , Paaby Annalise B.
Published: August 2021

The discovery that experimental delivery of dsRNA can induce gene silencing at target genes revolutionized genetics research, by both uncovering essential biological processes and creating new tools for developmental geneticists. However, the efficacy of exogenous RNAi varies dramatically within the C. elegans population, raising questions about our understanding of RNAi in the lab relative to its activity and significance in nature. Here, we investigate why some wild-type strains fail to mount a robust RNAi response to germline targets. We observe diversity in mechanism: in some strains, the response is stochastic, either on or off among individuals, while in others the response is consistent but delayed. Increased activity of the Argonaute PPW-1, which is required for germline RNAi in the laboratory strain N2, rescues the response in some strains, but dampens it further in others. Among wild-type strains, genes known to mediate RNAi exhibited very high expression variation relative to other genes in the genome as well as allelic divergence and strain-specific instances of pseudogenization at the sequence level. Our results demonstrate functional diversification in the small RNA pathways in C. elegans, and suggest that RNAi processes are evolving rapidly and dynamically in nature.
Polycomb Repressive Complex 2 shields naïve human pluripotent cells from trophectoderm differentiation
Authors: Kumar Banushree , Navarro Carmen , Winblad Nerges , Schell John P , Zhao Cheng , Lanner Fredrik , Elsässer Simon J
Published: August 2021

The first lineage choice made in human embryo development separates trophectoderm from the inner cell mass, which proceeds to form the pluripotent epiblast and primitive endoderm. Trophectoderm on the other hand gives rise to the placenta. Naïve pluripotent stem cells are derived from the pluripotent epiblast of the blastocyst and offer possibilities to explore how lineage integrity is maintained. Here, we discover that Polycomb repressive complex 2 (PRC2) restricts an intrinsic capacity of naïve pluripotent stem cells to give rise to trophectoderm. Through quantitative epigenome profiling, we find that broad histone H3 lysine 27 trimethylation (H3K27me3) hypermethylation is a common feature of naïve pluripotency across species. We define a previously unappreciated, naïve-specific set of bivalent promoters, featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm transcription factors in a transcriptionally poised state that is resolved to an active state upon depletion of H3K27me3 via inhibition of the enzymatic subunits of PRC2, EZH1/2. Conversely, primed human embryonic stem cells cannot be driven towards trophectoderm development via PRC2 inhibition. While naïve and primed hESCs share the majority of bivalent promoters, PRC2 contributes to the repression of largely non-overlapping subsets of these promoters in each state, hence H3K27me3-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.
Mechanistic basis for the emergence of EPS1 as a catalyst in plant salicylic acid biosynthesis
Authors: Torrens-Spence Michael P. , Li Tianjie , Wang Ziqi , Glinkerman Christopher M. , Matos Jason O. , Wang Yi , Weng Jing-Ke
Published: August 2021

Unique to plants in the Brassicaceae family, the production of the plant defense hormone salicylic acid (SA) from isochorismate is accelerated by an evolutionarily young isochorismoyl-glutamate pyruvoyl-glutamate lyase, EPS1, which belongs to the BAHD acyltransferase protein family. Here, we report the crystal structures of apo and substrate-analog-bound EPS1 from Arabidopsis thaliana. Assisted by microsecond molecular dynamics simulations, we uncover a unique pericyclic rearrangement lyase mechanism facilitated by the active site of EPS1. We reconstitute the isochorismate-derived pathway of SA biosynthesis in Saccharomyces cerevisiae, which serves as an in vivo platform that helps identify active-site residues critical for EPS1 activity. This study describes the birth of a new catalyst in plant phytohormone biosynthesis by reconfiguring the ancestral active site of a progenitor enzyme to catalyze alternative reaction.

One sentence summary

By reconfiguring the active site of a progenitor acyltransferase-fold, EPS1 acquired the unique, evolutionarily new lyase activity that accelerates phytohormone salicylic acid production in Brassicaceae plants.
Computational modeling of virucidal inhibition mechanism for broad-spectrum antiviral nanoparticles and HPV16 capsid segments
Authors: Chaturvedi Parth , Kelich Payam , Nitka Tara A. , Vuković Lela
Published: August 2021

Solid core nanoparticles coated with sulfonated ligands that mimic heparan sulfate proteoglycans (HSPG) can exhibit virucidal activity against many viruses that utilize HSPG interactions with host cells for the initial stages of the infection. How the interactions of these nanoparticles with large capsid segments of HSPG-interacting viruses lead to their virucidal activity has been unclear. Here, we describe the interactions between sulfonated nanoparticles and segments of the human papilloma virus type 16 (HPV16) capsids using atomistic molecular dynamics simulations. The simulations demonstrate that nanoparticles primarily bind at interfaces of two HPV16 capsid proteins. Insertions of nanoparticles at these interfaces leads to increased separation in distances and angles between capsid proteins. As the time progresses, the nanoparticle binding can lead to breaking of contacts between two neighboring proteins. The revealed mechanism of nanoparticles targeting the interfaces between pairs of capsid proteins can be utilized for designing new generations of virucidal materials and contribute to the development of new broad-spectrum non-toxic virucidal materials.

Abstract Figure
Electrical activity recorded from the spinal cord in freely moving rats using a subdural bioelectronic implant
Authors: Harland Bruce , Aqrawe Zaid , Vomero Maria , Boehler Christian , Raos Brad , Asplund Maria , O’Carroll Simon J , Svirskis Darren
Published: August 2021

Bioelectronic devices have found use at the interface with neural tissue to investigate and treat nervous system disorders. Here, we present the development and characterization of a thin flexible bioelectronic implant inserted over the thoracic spinal cord in rats directly in contact with the spinal cord. There was no negative impact on hind-limb functionality nor any change in the volume or shape of the spinal cord. The bioelectronic implant was maintained in rats for a period of 3 months. We present the first subdural recordings of spinal cord activity in freely moving animals. Recordings contained multiple distinct voltage waveform shapes that were typically between 1 – 6 mV and lasted between 0.1 and 1 seconds. In the future, this implant will facilitate the identification of biomarkers in spinal cord injury and recovery, while enabling the delivery of localized treatments.
Effects of face masks and ventilation on the risk of SARS-CoV-2 respiratory transmission in public toilets: a quantitative microbial risk assessment
Authors: Denpetkul Thammanitchpol , Sittipunsakda Oranoot , Pumkaew Monchai , Mongkolsuk Skorn , Sirikanchana Kwanrawee
Published: August 2021

Public toilets could increase the risk of COVID-19 infection via airborne transmission; however, related research is limited. We aimed to estimate SARS-CoV-2 infection risk through respiratory transmission using a quantitative microbial risk assessment framework by retrieving SARS-CoV-2 concentrations from the swab tests of 251 Thai patients. Three virus-generating scenarios were investigated: an infector breathing, breathing with a cough, and breathing with a sneeze. Infection risk (97.5th percentile) was as high as 10−3 with breathing and increased to 10−1 with a cough or sneeze, thus all higher than the risk benchmark of 5 × 10−5 per event. No significant gender differences for toilet users (receptors) were noted. The highest risk scenario of breathing and a sneeze was further evaluated for risk mitigation measures. Risk mitigation to lower than the benchmark succeeded only when the infector and receptor simultaneously wore an N95 respirator or surgical mask and when the receptor wore an N95 respirator and the infector wore a denim fabric mask. Ventilation up to 20 air changes per hour (ACH), beyond the 12-ACH suggested by the WHO, did not mitigate risk. Virus concentration, volume of expelled droplets, and receptor dwell time were identified as the main contributors to transmission risk.

Highlights

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The use of public toilets poses a risk of SARS-CoV-2 respiratory transmission

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Highest risks generated in the order of sneezing, coughing, and breathing

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No gender differences in risk by counteracting dwell times and inhalation rates

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Ventilation did not reduce risk even at 20 ACH, beyond the WHO-recommended value

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N95 and surgical masks offer the most effective risk mitigation to toilet users

Graphical abstract
Genotype-specific Features Reduce the Susceptibility of South American Yellow Fever Virus Strains to Vaccine-Induced Antibodies
Authors: Haslwanter Denise , Lasso Gorka , Wec Anna Z. , Furtado Nathália Dias , Raphael Lidiane Menezes Souza , Sun Yan , Stransky Stephanie , Pedreño-Lopez Núria , Tse Alexandra , Correia Carolina Argondizo , Bornholdt Zachary A. , Sakharkar Mrunal , Avelino-Silva Vivian I. , Moyer Crystal L. , Watkins David I. , Kallas Esper G. , Sidoli Simone , Walker Laura M. , Bonaldo Myrna C. , Chandran Kartik
Published: August 2021

The resurgence of yellow fever in South America has prompted mitigation through vaccination against the etiologic agent, yellow fever virus (YFV). Current vaccines are based on a virulent African isolate, and their capacity to induce neutralizing antibodies against the vaccine strain is widely used as a surrogate for protection. However, the sensitivity of genetically distinct South American strains to vaccine-induced antibodies is unknown. Here, we show that antiviral potency of the polyclonal antibody response in both U.S. and Brazilian vaccinees is attenuated against an emergent Brazilian strain. This reduction was attributable to genetic changes at two sites in the central domain II of the glycoprotein E, including the acquisition of an N–linked glycosylation site, which are unique to and shared among most South American YFV strains. Our findings call for a reevaluation of current approaches to YFV immunological surveillance in South America and suggest approaches for designing updated vaccines.
MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer
Authors: Prasad Manu , Zorea Jonathan , Jagadeeshan Sankar , Shnerb Avital , Bouaoud Jebrane , Michon Lucas , Novoplansky Ofra , Badarni Mai , Cohen Limor , Yagodayev Ksenia , Tzadok Sapir , Rotblat Barak , Brezina Libor , Mock Andreas , Karabajakian Andy , Fayette Jérôme , Cohen Idan , Cooks Tomer , Allon Irit , Dimitstei Orr , Joshua Benzion , Kong Dexin , Voronov Elena , Scaltriti Maurizio , Carmi Yaron , Hess Jochen , Morris Luc G.T. , Saintigny Pierre , Elkabets Moshe
Published: August 2021

Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+T cells. Further activation of CD8+T cells by supplementation with anti-programmed death-1 (αPD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction.

Graphical abstract
On the stability and layered organization of protein-DNA condensates
Authors: Latham Andrew P. , Zhang Bin
Published: August 2021

Multi-component phase separation is emerging as a key mechanism for the formation of biological condensates that play essential roles in signal sensing and transcriptional regulation. The molecular factors that dictate these condensates’ stability and spatial organization are not fully understood, and it remains challenging to predict their microstructures. Using a near-atomistic, chemically accurate force field, we studied the phase behavior of chromatin regulators that are crucial for heterochromatin organization and their interactions with DNA. Our computed phase diagrams recapitulated previous experimental findings on different proteins. They revealed a strong dependence of condensate stability on the protein-DNA mixing ratio as a result of balancing protein-protein interactions and charge neutralization. Notably, a layered organization was observed in condensates formed by mixing HP1, histone H1, and DNA. This layered organization may be of biological relevance as it enables cooperative DNA packaging between the two chromatin regulators: histone H1 softens the DNA to facilitate the compaction induced by HP1 droplets. Our study supports near atomistic models as a valuable tool for characterizing the structure and stability of biological condensates.
Structural and biochemical characterization of the novel serpin Iripin-5 from Ixodes ricinus
Authors: Kascakova Barbora , Kotal Jan , Martins Larissa Almeida , Berankova Zuzana , Langhansova Helena , Calvo Eric , Crossley Joel A. , Havlickova Petra , Dycka Filip , Prudnikova Tatyana , Kuty Michal , Kotsyfakis Michail , Chmelar Jindrich , Kuta Smatanova Ivana
Published: August 2021

Iripin-5 is the main Ixodes ricinus salivary serpin, which acts as a modulator of host defence mechanisms by impairing neutrophil migration, suppressing nitric oxide production by macrophages and altering complement functions. Iripin-5 influences host immunity and shows high expression in the salivary glands. Here, the crystal structure of Iripin-5 in the most thermodynamically stable state of serpins is described. In the reactive-centre loop, the main substrate-recognition site of Iripin-5 is likely to be represented by Arg342, which implies the targeting of trypsin-like proteases. Furthermore, a computational structural analysis of selected Iripin-5–protease complexes together with interface analysis revealed the most probable residues of Iripin-5 involved in complex formation.
Service marketing strategies and performances of tourism and hospitality enterprises: implications from a small border province in Thailand
Authors: Pholphirul Piriya , Rukumnuaykit Pungpond , Charoenrat Teerawat , Kwanyou Akkaranai , Srijamdee Kitisak
Published: August 2021

Purpose

The objective of this study is to determine how service marketing strategies affect enterprises in the tourism and hospitality industry, especially, operators in small towns that are not tourism destinations and visited only by small numbers of tourists.

Design/methodology/approach

This study investigates the impact of 4P strategy implementation on the potential and profitability of service operators in Nong Khai Province, Thailand, by using an econometric model and defining dependent variables in order to classify firm performance into 3 areas, namely, (1) revenue, (2) cost/expense and (3) profit—in log form.

Findings

Study results show that tourism and hospitality service operators have to place emphasis on “development,” starting from upstream processes such as research and development and utilizing local wisdom and reflecting cultural identities as well as focusing on downstream activities, including adoption of modern media. At the same time, operators should also emphasize marketing and sales promotions as well as seek publicity through websites and online social media in parallel with developing downstream activities.

Research limitations/implications

This paper only focuses on Nong Khai Province as the research area because, first, Nong Khai has a relatively low income per capita and is located in Thailand's Northeast, the country's poorest region. Second, Nong Khai is a border province, adjacent to the Lao PDR, and thus there are numerous tourists from the Lao PDR and overseas countries who travel in and out of the province through the Thailand–Lao border checkpoints.

Practical implications

Relevant government agencies should provide support throughout the development process from upstream to downstream in order to upgrade the potential of tourism and service operators in this small province by incorporating local identities used for creation of service products and by supporting marketing and sales promotions whether in the form of organizing various exhibitions events, publicity via the Internet, etc.

Social implications

Raising service standards of an organization and developing an acceptable quality brand and setting fair prices without taking advantage of consumers were strategies that played important roles. This set of strategies was implemented together with a development strategy for people also through the process of team building and knowledge management, including skill development through a training system, which also played an important role toward the sustainability of tourism and hospitality enterprises in Nong Khai Province.

Originality/value

It is believed that this paper is the first study to apply Stan Shih's innovation smiling curve in a small border province of Thailand. This study could shed the light for tourism and hospitality enterprises in a small and poor town in attempt to be the sustainability.
Social networks as a vehicle for happiness management in university governance
Authors: Barquero Cabrero José Daniel , Caldevilla Domínguez David , Barrientos Báez Almudena , Gonzálvez Vallés Juan Enrique
Published: August 2021

Purpose

This study aims to determine whether the communication of Universities in Madrid (Spain) on social networks through their official channels has caused positive results in students’ perceptions of their trust in university institutions during the first semester of the 2020–2021 term and to measure whether the implementation of happiness management strategies in the communication within university governance affected students’ happiness levels, as well as on the recognition of their belonging to the university.

Design/methodology/approach

With an exploratory-correlational approach and a quantitative study, this study conducted a statistical-descriptive analysis based on the premise of a general linear regression model with correlations between the variables, using a data collection instrument, whose construct and content validity was previously assessed by experts, which was answered by 564 students of the Degrees in Communication and Marketing from the Complutense University of Madrid, University of La Laguna, and ESERP Business and Law School. The Kaiser-Meyer-Olkin test and Bartlett’s test of sphericity were implemented to analyze the correlation between variables; Cronbach’s alpha coefficient and Pearson and Spearman’s coefficients were also used.

Findings

Those students who used social networks to receive news from university institutions about the COVID-19 pandemic deem these channels official, sound and credible. Similarly, the use of official information from university institutions on social networks increases students’ happiness levels.

Originality/value

To the best of the authors’ knowledge, this is one of the first studies aiming to provide scientific evidence of the relationship between happiness management and university governance. This research’s practical implications lead to attributing added value to these types of means for the university governance that seeks students’ happiness.
Managerial openness and employee voice: a moderated mediation model
Authors: Yin Yishuai , Duan Jinyun , Wang Tingxi , Jiao Xuhui
Published: August 2021

Purpose

Drawing on a costs-benefit analysis perspective, the purpose of this paper is to investigate the relationship between managerial openness and employee voice and its boundary conditions.

Design/methodology/approach

This study collected three waves of data by surveying 326 pairs of employees and their supervisors. The hypotheses were tested by using Hayes’s (2018) SPSS macro application with a bootstrap approach to obtain confidence intervals.

Findings

Managerial openness facilitates employee voice by decreasing perceived voice costs. Felt obligation positively moderates the direct as well as the indirect relationship between perceived voice costs and employee voice.

Originality/value

This study uncovers the alternative mechanism underlying the relationship between managerial openness and employee voice as well as the boundary condition of this relationship.
Theoretical analysis of entropy generation in second grade nanofluid considering heat source/sink over a rotating disk
Authors: Javed Muhammad Faisal , Jameel Mohammed , Khan Muhammad Ijaz , Qayyum Sumaira , Khan Niaz B. , Khan Tufail Ahmad
Published: August 2021

Purpose

This study aims to focus on second grade fluid flow over a rotating disk in the presence of chemical reaction. Uniform magnetic field is also taken into account. Because of the smaller magnetic Reynolds number, induced magnetic field is negligible. Heat equation is constructed by considering heat source/sink.

Design/methodology/approach

Suitable variables are used to transform nonlinear partial differential equations to ordinary ones. Convergent series solutions are attained by applying homotopy analysis method.

Findings

Trends of different parameters on concentration, velocity and temperature are shown graphically. Skin friction coefficient and local Nusselt number are calculated and investigated under the effect of elaborated parameters. An elevation in the value of magnetic field parameter causes collapse in the velocity distributions. Velocity distribution in increasing function of viscoelastic parameter. Temperature and concentration profiles are decreasing functions of viscoelastic parameter. Concentration distribution reduces by increasing the chemical reaction parameter. There is more surface drag force for larger M, while opposite behavior is noted for β.

Originality/value

To the best of the authors’ knowledge, such consideration is yet to be published in the literature.