bluuebunny/crossref_metadata_2025 huggingface dataset:
AUTOMORPHIC LEFSCHETZ PROPERTIES FOR NONCOMPACT ARITHMETIC MANIFOLDS
Authors: Nair Arvind N. , Rai Ankit
Published: October 2021

We prove the injectivity of Oda-type restriction maps for the cohomology of noncompact congruence quotients of symmetric spaces. This includes results for restriction between (1) congruence real hyperbolic manifolds, (2) congruence complex hyperbolic manifolds, and (3) orthogonal Shimura varieties. These results generalize results for compact congruence quotients by Bergeron and Clozel [Quelques conséquences des travaux d’Arthur pour le spectre et la topologie des variétés hyperboliques,Invent. Math.192(2013), 505–532] and Venkataramana [Cohomology of compact locally symmetric spaces,Compos. Math.125(2001), 221–253]. The proofs combine techniques of mixed Hodge theory and methods involving automorphic forms.
Untilted edge slot antennas excited by T-shaped wires
Authors: Moradian Mahdi
Published: October 2021

An effective method is proposed to excite the untilted edge slot antennas. In the proposed method, two T-shaped wires are placed at both sides of each untilted slot. Two legs of each T-shaped wire are connected to the waveguide walls, while the third leg is open. One of the T-shaped wires connects the upper broad wall of the waveguide to the narrow wall of the waveguide which contains the slots. Similarly, the other T-shaped wires connect the lower broad wall of the waveguide to the narrow wall of the waveguide that contains the slots. The phase reversal between the adjacent slots can be accomplished by changing the orientation of the T-shaped wires. It is shown that the arm lengths of the connected wires can be employed as a parameter to control the radiated power by the slots. Furthermore, the arm lengths of the open wires can be selected properly to control the dynamic range of the equivalent normalized susceptance associated with each untilted slot antenna. To validate the effectiveness of the proposed antennas, two linear arrays consisting of 11 slots have been designed, implemented, and tested. The simulation and the measurement results of the designed arrays show that for the proposed untilted edge slot antennas, the dynamic range of the equivalent normalized susceptance is improved significantly which leads to a straightforward design process with no requirement to resort to any time-consuming tuning process.
Birthweight and subsequent risk for thyroid and autoimmune conditions in postmenopausal women
Authors: Monahan Brian , Farland Leslie V. , Shadyab Aladdin H. , Hankinson Susan E. , Manson JoAnn E. , Spracklen Cassandra N.
Published: October 2021

The objective of this study was to determine the association between birthweight and risk of thyroid and autoimmune conditions in a large sample of postmenopausal women. Baseline data from the Women’s Health Initiative (n = 80,806) were used to examine the associations between birthweight category (<6 lbs., 6–7 lbs. 15 oz, 8–9 lbs. 15 oz, and ≥10 lbs.) and prevalent thyroid (underactive and overactive thyroid and goiter) and autoimmune (lupus, rheumatoid arthritis (RA), multiple sclerosis, ulcerative colitis/Crohn’s disease) conditions. Follow-up questionnaire data were used to examine the associations between birthweight and incident underactive and overactive thyroid, lupus, and RA. Logistic and Cox proportional hazards regression models were used to estimate crude and adjusted odds (OR) and hazards ratios (HR), respectively. Overall, women born weighing ≥10 lbs. had an increased risk for underactive thyroid [OR 1.14 (95% CI 1.02, 1.28)] and incident lupus [HR 1.51 (95% CI 1.12, 2.03)] and a decreased risk for overactive thyroid [OR 0.67 (95% CI 0.50, 0.92)] compared to women born weighing 6–7.99 lbs., after adjustment for adult BMI, demographic variables, and lifestyle factors. Further, women born weighing <6 lbs. were at increased risk for underactive thyroid [OR 1.13 (95% CI 1.04, 1.22)]. Birthweight was not associated with other thyroid or autoimmune disorders. High birthweight was associated with later-life thyroid and autoimmune conditions while low birthweight was associated with underactive thyroid. Preconception and prenatal interventions aimed at reducing the risk of both high and low birthweights may reduce the burden of later-life thyroid and autoimmune conditions.
Noble Gas Hints at Mars’s Rapid Formation
Authors: Japelj Jure
Published: October 2021

A new study finds that Mars’s mantle is neon-rich, putting constraints on the planet’s formation history.
The androgen receptor—lncRNASAT1-AKT-p15 axis mediates androgen-induced cellular senescence in prostate cancer cells
Authors: Mirzakhani Kimia , Kallenbach Julia , Rasa Seyed Mohammad Mahdi , Ribaudo Federico , Ungelenk Martin , Ehsani Marzieh , Gong Wenrong , Gassler Nikolaus , Leeder Mirjam , Grimm Marc-Oliver , Neri Francesco , Baniahmad Aria
Published: October 2021

The bipolar androgen therapy (BAT) to treat prostate cancer (PCa) includes cycles of supraphysiological androgen levels (SAL) under androgen-deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and in ex vivo-treated patient PCa tumor samples. Here, we analyzed the underlying molecular pathway and reveal that SAL induces cellular senescence in both, castration-sensitive (CSPC) LNCaP and castration-resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15INK4b and increased phosphorylation of AKT. Treatment with the AKT inhibitor (AKTi) potently inhibited SAL-induced expression of p15INK4b and cellular senescence in both cell lines. Proximity-ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with AKT in the cytoplasm as well as in the nucleus detectable after three days. Transcriptome sequencing (RNA-seq) comparing the SAL-induced transcriptomes of LNCaP with C4-2 cells as well as with AKTi-treated cell transcriptomes revealed landscapes for cell senescence. Interestingly, one of the identified genes is the lncRNASAT1. SAL treatment of native patient tumor samples ex vivo upregulates lncRNASAT1. In PCa tumor tissues, lncRNASAT1 is downregulated compared with nontumor tissues of the same patients. Knockdown indicates that the lncRNASAT1 is crucial for SAL-induced cancer-cell senescence as an upstream factor for pAKT and for p15INK4b. Further, knockdown of lncRNASAT1 enhances cell proliferation by SAL, suggesting that lncRNASAT1 serves as a tumor suppressor at SAL. Interestingly, immunoprecipitation of AR detected lncRNASAT1 as an AR-interacting partner that regulates AR target-gene expression. Similarly, RNA-ChIP experiments revealed the interaction of AR with lncRNASAT1 on chromatin. Thus, we identified a novel AR-lncRNASAT1-AKT-p15INK4b signaling axis to mediate SAL-induced cellular senescence.
Gene expression profiling in peripheral blood lymphocytes for major depression: preliminary cues from Chinese discordant sib-pair study
Authors: Wu Chan , Wang Danfeng , Niu Kangkang , Feng Qili , Chen Hanwei , Zhu Haibing , Xiang Hui
Published: October 2021

The etiology of major depressive disorder (MDD) involves many factors such as heredity and environment. There are very few MDD-related studies in Chinese population using twin or sib-pairs for depression-control samples. Here we used the microarray approach and compared gene expression profiling of peripheral blood lymphocytes from 6 sib-pairs discordant on lifetime history of MDD. Within sib-pair differentially expressed genes are obvious fewer in the 1st, 2nd, and 5th compared with those in the 3rd, 4th, and 6th sib-pairs. Gene expression pattern of these DEGs distinguished MDD individuals from the normal one in 3rd, 4th, and 6th sib-pair but not in the 1st, 2nd, and 5th pair, suggesting heterogeneity of different sib-pairs and somewhat commonalities among the 3rd, 4th, and 6th sib-pairs. Comprehensive protein interaction network analysis revealed two key genes PTH and FGF2 in a dominant network where the majority of the genes were significantly down-regulated. PTH was significantly down-regulated in all the sib-pairs while FGF2 was in the 3rd, 4th, and 6th sib-pairs. KEGG enrichment analysis of all the DEGs in networks showed that PTH and related genes were significantly enriched in the pathway of parathyroid hormone secretion, synthesis, and action while FGF2 and related genes were significantly enriched in the pathways of cancer and specifically breast cancer. Generally reduced expression of these genes in peripheral blood lymphocytes of MDD individuals implied their functional repression associated with MDD. Pending validation in more samples, the findings in this study provided valuable cues for understanding the potential mechanism of MDD, as well as potential markers for the diagnosis and treatment of depression in the Chinese population.
ERp29 forms a feedback regulation loop with microRNA-135a-5p and promotes progression of colorectal cancer
Authors: Huang Jiebin , Jing Mengxia , Chen Xixi , Gao Yuanqi , Hua Huiying , Pan Chun , Wu Jing , Wang Xinqiong , Chen Xuehua , Gao Yujing , Xu Chundi , Li Pu
Published: October 2021

Expression of endoplasmic reticulum (ER) stress-associated genes is often dysregulated in cancer progression. ER protein 29 (ERp29) is abnormally expressed in many neoplasms and plays an important role in tumorigenesis. Here, we showed ERp29 is a novel target for microRNA-135a-5p (miR-135a-5p) to inhibit the progression of colorectal cancer (CRC); correspondingly, ERp29 acts as an oncoprotein in CRC by promoting proliferation and metastasis of CRC cells, and suppressing apoptosis of the cells. More importantly, we found that miR-135a-5p expression is reversely upregulated by ERp29 through suppressing IL-1β-elicited methylation of miR-135a-5p promoter region, a process for enterocyte to maintain a balance between miR-135a-5p and ERp29 but dysregulated in CRC. Our study reveals a novel feedback regulation loop between miR-135a-5p and ERp29 that is critical for maintaining appropriate level of each of them, but partially imbalanced in CRC, resulting in abnormal expression of miR-135a-5p and ERp29, which further accelerates CRC progression. We provide supporting evidence for ERp29 and miR-135a-5p as potential biomarkers for diagnosis and treatment of CRC.
Histone demethylase KDM4D inhibition suppresses renal cancer progression and angiogenesis through JAG1 signaling
Authors: Yan Hao , Zhu Liangsong , Zhang Jin , Lin Zongming
Published: October 2021

Kidney cancer, especially clear cell renal cell carcinoma (ccRCC), is one of the representative genitourinary tumors. Investigation of underlying mechanisms of ccRCC development is crucial for patient management. Histone demethylase KDM4D has been reported to be responsible for development of a variety of cancers. However, the role of KDM4D in ccRCC progression is poorly understood. In our study, we performed immunohistochemistry analysis of tissue microarrays first, and results showed that high expression level of KDM4D is connected with advanced Fuhrman grade (p = 0.0118) and lower overall survival (p = 0.0020). Then, we revealed that KDM4D can prompt ccRCC development by interacting with genes related to vessel morphogenesis. Finally, we disclosed that KDM4D directly interacts with JAG1 promoter and advances tumor angiogenesis by upregulating VEGFR-3 and antagonizing notch signaling. The results of our study indicate that KDM4D would be a potential prognostic marker and therapeutic target for ccRCC patients.
TM7SF2 regulates cell proliferation and apoptosis by activation of C-Raf/ERK pathway in cervical cancer
Authors: Xu Yichi , Chen Xin , Pan Shuya , Wang Zhi-wei , Zhu Xueqiong
Published: October 2021

Transmembrane 7 superfamily member 2 (TM7SF2) coding an enzyme involved in cholesterol metabolism has been found to be differentially expressed in kinds of tissues. Nevertheless, the role of TM7SF2 in the regulation of growth and progression among various cancers is unclear. In this study, the immunohistochemistry (IHC) assay, real-time RT-PCR and western blotting analysis were used to determine the TM7SF2 expression in cervical cancer tissues. Next, we used multiple methods to determine the ability of cell proliferation, migration, invasion, apoptosis, and cell cycle in cervical cancer cells after TM7SF2 modulation, such as CCK8 assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry. Our results revealed that upregulation of TM7SF2 facilitated cell proliferation and metastasis, suppressed cell apoptosis and prevented G0/G1 phase arrests in C33A and SiHa cells. Consistently, the opposite effects were observed after TM7SF2 knockout in cervical cancer cells. Further, we found that TM7SF2 participated in promoting tumorigenesis and progression via activation of C-Raf/ERK pathway in cervical cancer, which can be partly reversed by Raf inhibitor LY3009120. Moreover, TM7SF2 overexpression contributed to enhancement of xenograft tumor growth in vivo. Our findings indicated that TM7SF2 plays a vital role in tumor promotion by involving in C-Raf/ERK activation. Therefore, TM7SF2 could serve as a therapeutic target in future cervical cancer treatment.
RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α–XBP1s pathway
Authors: Wang Jia-Wei , Ma Li , Liang Yuan , Yang Xiao-Jun , Wei Song , Peng Hao , Qiu Shi-Pei , Lu Xu , Zhu Ya-Qing , Wang Bao-Lin
Published: October 2021

The increasing incidence of hepatocellular carcinoma (HCC) is of great concern globally, but the molecular pathogenesis of these tumors remains unclear. Sorafenib is a first-line drug for the treatment of advanced HCC. However, the efficacy of sorafenib in improving patient survival is limited, and most patients inevitably develop resistance to this drug. Recent studies have demonstrated that the activation of the IRE1α–XBP1s pathway might play a protective role in the response to sorafenib and contribute to malignancy in HCC. Here, we found that RCN1, an endoplasmic reticulum resident protein, is significantly upregulated in sorafenib-resistant HCC cells and promotes tumor progression. Our analysis showed that RCN1 may be an independent predictor of tumor recurrence and overall survival. Mechanistically, RCN1 promotes the dissociation of GRP78 from IRE1α in sorafenib-resistant cells by interacting with GRP78 through its EFh1/2 domain. Subsequently, the IRE1α–XBP1s pathway, a branch of the unfolded protein response, is sustainably activated. Interestingly, IRE1α–XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in HCC. These results suggest that RCN1-targeted therapy might be a feasible strategy for the treatment of HCC.
Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis
Authors: Liao Min , Dong Qiongye , Chen Ruiqing , Xu Liqian , Jiang Yuxuan , Guo Zhenxing , Xiao Min , He Wei , Cao Changcai , Hu Ronghua , Sun Wanling , Jiang Hong , Wang Jianwei
Published: October 2021

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC50 = 2.1 µM) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.
Fast ion transport for synthesis and stabilization of β-Zn4Sb3
Authors: Yang Dongwang , Su Xianli , He Jian , Yan Yonggao , Li Jun , Bai Hui , Luo Tingting , Liu Yamei , Luo Hao , Yu Yimeng , Wu Jinsong , Zhang Qingjie , Uher Ctirad , Tang Xinfeng
Published: October 2021

Mobile ion-enabled phenomena make β-Zn4Sb3 a promising material in terms of the re-entry phase instability behavior, mixed electronic ionic conduction, and thermoelectric performance. Here, we utilize the fast Zn2+ migration under a sawtooth waveform electric field and a dynamical growth of 3-dimensional ionic conduction network to achieve ultra-fast synthesis of β-Zn4Sb3. Moreover, the interplay between the mobile ions, electric field, and temperature field gives rise to exquisite core-shell crystalline-amorphous microstructures that self-adaptively stabilize β-Zn4Sb3. Doping Cd or Ge on the Zn site as steric hindrance further stabilizes β-Zn4Sb3 by restricting long-range Zn2+ migration and extends the operation temperature range of high thermoelectric performance. These results provide insight into the development of mixed-conduction thermoelectric materials, batteries, and other functional materials.
A dual-reporter system for investigating and optimizing protein translation and folding in E. coli
Authors: Zutz Ariane , Hamborg Louise , Pedersen Lasse Ebdrup , Kassem Maher M. , Papaleo Elena , Koza Anna , Herrgård Markus J. , Jensen Sheila Ingemann , Teilum Kaare , Lindorff-Larsen Kresten , Nielsen Alex Toftgaard
Published: October 2021

Strategies for investigating and optimizing the expression and folding of proteins for biotechnological and pharmaceutical purposes are in high demand. Here, we describe a dual-reporter biosensor system that simultaneously assesses in vivo protein translation and protein folding, thereby enabling rapid screening of mutant libraries. We have validated the dual-reporter system on five different proteins and find an excellent correlation between reporter signals and the levels of protein expression and solubility of the proteins. We further demonstrate the applicability of the dual-reporter system as a screening assay for deep mutational scanning experiments. The system enables high throughput selection of protein variants with high expression levels and altered protein stability. Next generation sequencing analysis of the resulting libraries of protein variants show a good correlation between computationally predicted and experimentally determined protein stabilities. We furthermore show that the mutational experimental data obtained using this system may be useful for protein structure calculations.
De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories
Authors: Liu Quanli , Liu Yi , Li Gang , Savolainen Otto , Chen Yun , Nielsen Jens
Published: October 2021

Isoflavonoids comprise a class of plant natural products with great nutraceutical, pharmaceutical and agricultural significance. Their low abundance in nature and structural complexity however hampers access to these phytochemicals through traditional crop-based manufacturing or chemical synthesis. Microbial bioproduction therefore represents an attractive alternative. Here, we engineer the metabolism of Saccharomyces cerevisiae to become a platform for efficient production of daidzein, a core chemical scaffold for isoflavonoid biosynthesis, and demonstrate its application towards producing bioactive glucosides from glucose, following the screening-reconstruction-application engineering framework. First, we rebuild daidzein biosynthesis in yeast and its production is then improved by 94-fold through screening biosynthetic enzymes, identifying rate-limiting steps, implementing dynamic control, engineering substrate trafficking and fine-tuning competing metabolic processes. The optimized strain produces up to 85.4 mg L−1 of daidzein and introducing plant glycosyltransferases in this strain results in production of bioactive puerarin (72.8 mg L−1) and daidzin (73.2 mg L−1). Our work provides a promising step towards developing synthetic yeast cell factories for de novo biosynthesis of value-added isoflavonoids and the multi-phased framework may be extended to engineer pathways of complex natural products in other microbial hosts.
Transcriptome profiling of pepper leaves by RNA-Seq during an incompatible and a compatible pepper-tobamovirus interaction
Authors: Kalapos Balázs , Juhász Csilla , Balogh Eszter , Kocsy Gábor , Tóbiás István , Gullner Gábor
Published: October 2021

Upon virus infections, the rapid and comprehensive transcriptional reprogramming in host plant cells is critical to ward off virus attack. To uncover genes and defense pathways that are associated with virus resistance, we carried out the transcriptome-wide Illumina RNA-Seq analysis of pepper leaves harboring the L3 resistance gene at 4, 8, 24 and 48 h post-inoculation (hpi) with two tobamoviruses. Obuda pepper virus (ObPV) inoculation led to hypersensitive reaction (incompatible interaction), while Pepper mild mottle virus (PMMoV) inoculation resulted in a systemic infection without visible symptoms (compatible interaction). ObPV induced robust changes in the pepper transcriptome, whereas PMMoV showed much weaker effects. ObPV markedly suppressed genes related to photosynthesis, carbon fixation and photorespiration. On the other hand, genes associated with energy producing pathways, immune receptors, signaling cascades, transcription factors, pathogenesis-related proteins, enzymes of terpenoid biosynthesis and ethylene metabolism as well as glutathione S-transferases were markedly activated by ObPV. Genes related to photosynthesis and carbon fixation were slightly suppressed also by PMMoV. However, PMMoV did not influence significantly the disease signaling and defense pathways. RNA-Seq results were validated by real-time qPCR for ten pepper genes. Our findings provide a deeper insight into defense mechanisms underlying tobamovirus resistance in pepper.
H3K23/H3K36 hypoacetylation and HDAC1 up-regulation are associated with adverse consequences in obstructive sleep apnea patients
Authors: Chen Yung-Che , Hsu Po-Yuan , Chin Chien-Hung , Hsiao Chang-Chun , Liou Chia-Wei , Wang Ting-Ya , Lin Yong-Yong , Lee Chiu-Ping , Lin Hsin-Ching , Lin Meng-Chih , Su Mao-Chang
Published: October 2021

The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.
Pseudomonas aeruginosa transcriptome adaptations from colonization to biofilm infection of skin wounds
Authors: D’Arpa Peter , Karna S. L. Rajasekhar , Chen Tsute , Leung Kai P.
Published: October 2021

In burn patients Pseudomonas aeruginosa infection is a major cause of morbidity. Analysis of the pathogen’s gene expression as it transitions from colonization to acute and then biofilm wound infection may provide strategies for infection control. Toward this goal, we seeded log-phase P. aeruginosa (PAO1) into 3-day-old, full-thickness excision wounds (rabbit ear) and harvested the bacteria during colonization (Hrs 2 and 6), acute infection (Hr 24), and biofilm infection (Days 5 and 9) for transcriptome analysis (RNA-Seq). After 2–6 h in the wound, genes for metabolism and cell replication were down-regulated while wound-adaptation genes were up-regulated (vs. expression in log-phase culture). As the infection progressed from acute to biofilm infection, more genes became up-regulated than down-regulated, but the down-regulated genes enriched in more pathways, likely because the genes and pathways that bacteria already colonizing wounds up-regulate to establish biofilm infection are less known. Across the stages of infection, carbon-utilization pathways shifted. During acute infection, itaconate produced by myeloid cells appears to have been a carbon source because myeloid cell infiltration and the expression of the host gene, ACOD1, for itaconate production peaked coincidently with the expression of the PAO1 genes for itaconate transport and catabolism. Additionally, branched-chain amino acids are suggested to be a carbon source in acute infection and in biofilm infection. In biofilm infection, fatty acid degradation was also up-regulated. These carbon sources feed into the glyoxylate cycle that was coincidently up-regulated, suggesting it provided the precursors for P. aeruginosa to synthesize macromolecules in establishing wound infection.
Domestic risk factors for increased rodent abundance in a Lassa fever endemic region of rural Upper Guinea
Authors: Clark Julia , Yakob Laith , Douno Moussa , Lamine Joseph , Magassouba N.’Faly , Fichet-Calvet Elisabeth , Mari-Saez Almudena
Published: October 2021

Lassa fever (LF) is a viral haemorrhagic fever endemic in West Africa and spread primarily by the multimammate rat,Mastomys natalensis. As there is no vaccine, reduction of rodent-human transmission is essential for disease control. As the household is thought to be a key site of transmission, understanding domestic risk factors forM. natalensisabundance is crucial. Rodent captures in conjunction with domestic surveys were carried out in 6 villages in an area of rural Upper Guinea with high LF endemicity. 120 rodent traps were set in rooms along a transect in each village for three nights, and the survey was administered in each household on the transects. This study was able to detect several domestic risk factors for increased rodent abundance in rural Upper Guinea. Regression analysis demonstrated that having > 8 holes (RR = 1.8 [1.0004–3.2, p = 0.048), the presence of rodent burrows (RR = 2.3 [1.6–3.23, p = 0.000003), and being in a multi-room square building (RR = 2.0 [1.3–2.9], p = 0.001) were associated with increased rodent abundance. The most addressable of these may be rodent burrows, as burrow patching is a relatively simple process that may reduce rodent entry. Further study is warranted to explicitly link domestic rodent abundance to LF risk, to better characterize domestic risk factors, and to evaluate how household rodent-proofing interventions could contribute to LF control.
Deep Bayesian Gaussian processes for uncertainty estimation in electronic health records
Authors: Li Yikuan , Rao Shishir , Hassaine Abdelaali , Ramakrishnan Rema , Canoy Dexter , Salimi-Khorshidi Gholamreza , Mamouei Mohammad , Lukasiewicz Thomas , Rahimi Kazem
Published: October 2021

One major impediment to the wider use of deep learning for clinical decision making is the difficulty of assigning a level of confidence to model predictions. Currently, deep Bayesian neural networks and sparse Gaussian processes are the main two scalable uncertainty estimation methods. However, deep Bayesian neural networks suffer from lack of expressiveness, and more expressive models such as deep kernel learning, which is an extension of sparse Gaussian process, captures only the uncertainty from the higher-level latent space. Therefore, the deep learning model under it lacks interpretability and ignores uncertainty from the raw data. In this paper, we merge features of the deep Bayesian learning framework with deep kernel learning to leverage the strengths of both methods for a more comprehensive uncertainty estimation. Through a series of experiments on predicting the first incidence of heart failure, diabetes and depression applied to large-scale electronic medical records, we demonstrate that our method is better at capturing uncertainty than both Gaussian processes and deep Bayesian neural networks in terms of indicating data insufficiency and identifying misclassifications, with a comparable generalization performance. Furthermore, by assessing the accuracy and area under the receiver operating characteristic curve over the predictive probability, we show that our method is less susceptible to making overconfident predictions, especially for the minority class in imbalanced datasets. Finally, we demonstrate how uncertainty information derived by the model can inform risk factor analysis towards model interpretability.
Effects of global warming on Mediterranean coral forests
Authors: Chimienti Giovanni , De Padova Diana , Adamo Maria , Mossa Michele , Bottalico Antonella , Lisco Anna , Ungaro Nicola , Mastrototaro Francesco
Published: October 2021

The effects of global warming have been addressed on coral reefs in tropical areas, while it is still unclear how coral forests are reacting, particularly at temperate latitudes. Here we show how mesophotic coral forests are affected by global warming in the Mediterranean Sea. We highlight how the current warming trend is causing the lowering of the thermocline and it is enhancing mucilaginous blooms. These stressors are facilitating a massive macroalgal epibiosis on living corals, here reported for the first time from different areas in the Western and Central Mediterranean Sea. We provide a focus of this phenomenon at Tremiti Islands Marine Protected Area (Adriatic Sea), were the density of the endemic red gorgonian Paramuricea clavata decreased of up to 47% in 5 years, while up to the 96% of the living corals showed signs of stress and macroalgal epibiosis. Only populations deeper than 60 m depth were not touched by this emerging phenomenon. Spot observations performed at Tuscan Archipelago and Tavolara Marine Protected Area (Tyrrhenian Sea) suggest that this this combination of stressors is likely widespread at basin scale.
The accuracy of several pose estimation methods for 3D joint centre localisation
Authors: Needham Laurie , Evans Murray , Cosker Darren P. , Wade Logan , McGuigan Polly M. , Bilzon James L. , Colyer Steffi L.
Published: October 2021

Human movement researchers are often restricted to laboratory environments and data capture techniques that are time and/or resource intensive. Markerless pose estimation algorithms show great potential to facilitate large scale movement studies ‘in the wild’, i.e., outside of the constraints imposed by marker-based motion capture. However, the accuracy of such algorithms has not yet been fully evaluated. We computed 3D joint centre locations using several pre-trained deep-learning based pose estimation methods (OpenPose, AlphaPose, DeepLabCut) and compared to marker-based motion capture. Participants performed walking, running and jumping activities while marker-based motion capture data and multi-camera high speed images (200 Hz) were captured. The pose estimation algorithms were applied to 2D image data and 3D joint centre locations were reconstructed. Pose estimation derived joint centres demonstrated systematic differences at the hip and knee (~ 30–50 mm), most likely due to mislabeling of ground truth data in the training datasets. Where systematic differences were lower, e.g., the ankle, differences of 1–15 mm were observed depending on the activity. Markerless motion capture represents a highly promising emerging technology that could free movement scientists from laboratory environments but 3D joint centre locations are not yet consistently comparable to marker-based motion capture.
Mouse Dspp frameshift model of human dentinogenesis imperfecta
Authors: Liang Tian , Hu Yuanyuan , Zhang Hong , Xu Qian , Smith Charles E. , Zhang Chuhua , Kim Jung-Wook , Wang Shih-Kai , Saunders Thomas L. , Lu Yongbo , Hu Jan C.-C. , Simmer James P.
Published: October 2021

Non-syndromic inherited defects of tooth dentin are caused by two classes of dominant negative/gain-of-function mutations in dentin sialophosphoprotein (DSPP): 5′ mutations affecting an N-terminal targeting sequence and 3′ mutations that shift translation into the − 1 reading frame. DSPP defects cause an overlapping spectrum of phenotypes classified as dentin dysplasia type II and dentinogenesis imperfecta types II and III. Using CRISPR/Cas9, we generated a Dspp−1fs mouse model by introducing a FLAG-tag followed by a single nucleotide deletion that translated 493 extraneous amino acids before termination. Developing incisors and/or molars from this mouse and a DsppP19L mouse were characterized by morphological assessment, bSEM, nanohardness testing, histological analysis, in situ hybridization and immunohistochemistry. DsppP19L dentin contained dentinal tubules but grew slowly and was softer and less mineralized than the wild-type. DsppP19L incisor enamel was softer than normal, while molar enamel showed reduced rod/interrod definition. Dspp−1fs dentin formation was analogous to reparative dentin: it lacked dentinal tubules, contained cellular debris, and was significantly softer and thinner than Dspp+/+ and DsppP19L dentin. The Dspp−1fs incisor enamel appeared normal and was comparable to the wild-type in hardness. We conclude that 5′ and 3′ Dspp mutations cause dental malformations through different pathological mechanisms and can be regarded as distinct disorders.
Integrated computational analyses reveal novel insights into the stromal microenvironment of SHH-subtype medulloblastoma
Authors: Landry Alexander P. , Samuel Nardin , Spears Julian , Zador Zsolt
Published: October 2021

Medulloblastoma is the most common malignant brain tumour of childhood. While our understanding of this disease has progressed substantially in recent years, the role of tumour microenvironment remains unclear. Given the increasing role of microenvironment-targeted therapeutics in other cancers, this study was aimed at further exploring its role in medulloblastoma. Multiple computational techniques were used to analyze open-source bulk and single cell RNA seq data from primary samples derived from all subgroups of medulloblastoma. Gene expression is used to infer stromal subpopulations, and network-based approaches are used to identify potential therapeutic targets. Bulk data was obtained from 763 medulloblastoma samples and single cell data from an additional 7241 cells from 23 tumours. Independent bulk (285 tumours) and single cell (32,868 cells from 29 tumours) validation cohorts were used to verify results. The SHH subgroup was found to be enriched in stromal activity, including the epithelial-to-mesenchymal transition, while group 3 is comparatively stroma-suppressed. Several receptor and ligand candidates underlying this difference are identified which we find to correlate with metastatic potential of SHH medulloblastoma. Additionally, a biologically active gradient is detected within SHH medulloblastoma, from “stroma-active” to “stroma-suppressed” cells which may have relevance to targeted therapy. This study serves to further elucidate the role of the stromal microenvironment in SHH-subgroup medulloblastoma and identify novel treatment possibilities for this challenging disease.
Non-destructive mid-IR spectroscopy with quantum cascade laser can detect ethylene gas dynamics of apple cultivar ‘Fuji’ in real time
Authors: Yumoto Masaki , Kawata Yasushi , Abe Tetsuya , Matsuyama Tomoki , Wada Satoshi
Published: October 2021

Many plants, including fruits and vegetables, release biogenic gases containing various volatile organic compounds such as ethylene (C2H4), which is a gaseous phytohormone. Non-destructive and in-situ gas sampling technology to detect trace C2H4 released from plants in real time would be attractive for visualising the ageing, ripening, and defence reactions of plants. In this study, we developed a C2H4 detection system with a detection limit of 0.8 ppb (3σ) using laser absorption spectroscopy. The C2H4 detection system consists of a mid-infrared quantum cascade laser oscillated at 10.5 µm, a multi-pass gas cell, a mid-IR photodetector, and a gas sampling system. Using non-destructive and in-situ gas sampling, while maintaining the internal pressure of the multi-pass gas cell at low pressure, the change in trace C2H4 concentration released from apples (Malus domestica Borkh.) can be observed in real time. We succeeded in observing C2H4 concentration changes with a time resolution of 1 s, while changing the atmospheric gas and surface temperature of apples from the ‘Fuji’ cultivar. This technique allows the visualisation of detailed C2H4 dynamics in plant environmental response, which may be promising for further progress in plant physiology, agriculture, and food science.
Identification of serum prognostic biomarkers of severe COVID-19 using a quantitative proteomic approach
Authors: Kimura Yayoi , Nakai Yusuke , Shin Jihye , Hara Miyui , Takeda Yuriko , Kubo Sousuke , Jeremiah Sundararaj Stanleyraj , Ino Yoko , Akiyama Tomoko , Moriyama Kayano , Sakai Kazuya , Saji Ryo , Nishii Mototsugu , Kitamura Hideya , Murohashi Kota , Yamamoto Kouji , Kaneko Takeshi , Takeuchi Ichiro , Hagiwara Eri , Ogura Takashi , Hasegawa Hideki , Tamura Tomohiko , Yamanaka Takeharu , Ryo Akihide
Published: October 2021

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.
Optimization of fish gelatin drying processes and characterization of its properties
Authors: da Silva Araújo Cleidiane , Pino-Hernández Enrique , Souza Batista Jáira Thayse , Sarkis Peixoto Joele Maria Regina , de Arimateia Rodrigues do Rego José , Henriques Lourenço Lúcia de Fátima
Published: October 2021

Fish skin is a raw material used for gelatin production. It can satisfy consumers with specific socio-cultural and religious needs. Different technologies have been studied for drying gelatin. Therefore, it is relevant to understand the influence of drying conditions on the final product. This study aims to optimize drying methods such as convection hot air alone and combined with infrared radiation to obtain gelatin from acoupa weakfish skin by using composite central rotational designs 22 and 23 and response surface methodology. The gelatin obtained from the optimized conditions were characterized based on their physical, chemical, technological, and functional properties. The desirability function results show the convection hot air as the most effective method when conducted at 59.14 °C for 12.35 h. Infrared radiation at 70 °C for 2.0 h and convective drying at 70 °C for 3.5 h were the best condition of the combined process. The gelatins obtained had gel strength of 298.00 and 507.33 g and emulsion activity index of 82.46 and 62.77 m2/g in the combined and convective methods, respectively, and protein content above 90%. These results indicate that the processes studied can be used to produce gelatin with suitable technological and functional properties for several applications.
A compact platform for the investigation of material dynamics in quasi-isentropic compression to ~ 19 GPa
Authors: Lu Yu , Chen Kaiguo , Cheng Cheng , Zhou Zhongyu , Luo Binqiang , Chen Xuemiao , Zhang Xuping , Wang Guiji , Tan Fuli , Zhao Jianheng , Gu Zhuowei , Sun Chengwei
Published: October 2021

This paper reports on the development of a magnetically driven high-velocity implosion experiment conducted on the CQ-3 facility, a compact pulsed power generator with a load current of 2.1 MA. The current generates a high Lorentz force between inner and outer liners made from 2024 aluminum. Equally positioned photonic Doppler velocimetry probes record the liner velocities. In experiment CQ3-Shot137, the inner liner imploded with a radial converging velocity of 6.57 km/s while the outer liner expanded at a much lower velocity. One-dimensional magneto-hydrodynamics simulation with proper material models provided curves of velocity versus time that agree well with the experimental measurements. Simulation then shows that the inner liner underwent a shock-less compression to approximately 19 GPa and reached an off-Hugoniot high-pressure state. According to the scaling law that the maximum loading pressure is proportional to the square of the load current amplitude, the results demonstrate that such a compact capacitor bank as CQ-3 has the potential to generate pressure as high as 100 GPa within the inner liner in such an implosion experiment. It is emphasized that the technique described in this paper can be easily replicated at low cost.
Uncovering of intraspecies macular heterogeneity in cynomolgus monkeys using hybrid machine learning optical coherence tomography image segmentation
Authors: Maloca Peter M. , Seeger Christine , Booler Helen , Valmaggia Philippe , Kawamoto Ken , Kaba Qayim , Inglin Nadja , Balaskas Konstantinos , Egan Catherine , Tufail Adnan , Scholl Hendrik P. N. , Hasler Pascal W. , Denk Nora
Published: October 2021

The fovea is a depression in the center of the macula and is the site of the highest visual acuity. Optical coherence tomography (OCT) has contributed considerably in elucidating the pathologic changes in the fovea and is now being considered as an accompanying imaging method in drug development, such as antivascular endothelial growth factor and its safety profiling. Because animal numbers are limited in preclinical studies and automatized image evaluation tools have not yet been routinely employed, essential reference data describing the morphologic variations in macular thickness in laboratory cynomolgus monkeys are sparse to nonexistent. A hybrid machine learning algorithm was applied for automated OCT image processing and measurements of central retina thickness and surface area values. Morphological variations and the effects of sex and geographical origin were determined. Based on our findings, the fovea parameters are specific to the geographic origin. Despite morphological similarities among cynomolgus monkeys, considerable variations in the foveolar contour, even within the same species but from different geographic origins, were found. The results of the reference database show that not only the entire retinal thickness, but also the macular subfields, should be considered when designing preclinical studies and in the interpretation of foveal data.
Characterizing human random-sequence generation in competitive and non-competitive environments using Lempel–Ziv complexity
Authors: Wong Alice , Merholz Garance , Maoz Uri
Published: October 2021

The human ability for random-sequence generation (RSG) is limited but improves in a competitive game environment with feedback. However, it remains unclear how random people can be during games and whether RSG during games can improve when explicitly informing people that they must be as random as possible to win the game. Nor is it known whether any such improvement in RSG transfers outside the game environment. To investigate this, we designed a pre/post intervention paradigm around a Rock-Paper-Scissors game followed by a questionnaire. During the game, we manipulated participants’ level of awareness of the computer’s strategy; they were either (a) not informed of the computer’s algorithm or (b) explicitly informed that the computer used patterns in their choice history against them, so they must be maximally random to win. Using a compressibility metric of randomness, our results demonstrate that human RSG can reach levels statistically indistinguishable from computer pseudo-random generators in a competitive-game setting. However, our results also suggest that human RSG cannot be further improved by explicitly informing participants that they need to be random to win. In addition, the higher RSG in the game setting does not transfer outside the game environment. Furthermore, we found that the underrepresentation of long repetitions of the same entry in the series explains up to 29% of the variability in human RSG, and we discuss what might make up the variance left unexplained.
A deep learning model for classifying human facial expressions from infrared thermal images
Authors: Bhattacharyya Ankan , Chatterjee Somnath , Sen Shibaprasad , Sinitca Aleksandr , Kaplun Dmitrii , Sarkar Ram
Published: October 2021

The analysis of human facial expressions from the thermal images captured by the Infrared Thermal Imaging (IRTI) cameras has recently gained importance compared to images captured by the standard cameras using light having a wavelength in the visible spectrum. It is because infrared cameras work well in low-light conditions and also infrared spectrum captures thermal distribution that is very useful for building systems like Robot interaction systems, quantifying the cognitive responses from facial expressions, disease control, etc. In this paper, a deep learning model calledIRFacExNet(InfraRedFacialExpressionNetwork) has been proposed for facial expression recognition (FER) from infrared images. It utilizes two building blocks namely Residual unit and Transformation unit which extract dominant features from the input images specific to the expressions. The extracted features help to detect the emotion of the subjects in consideration accurately. The Snapshot ensemble technique is adopted with a Cosine annealing learning rate scheduler to improve the overall performance. The performance of the proposed model has been evaluated on a publicly available dataset, namelyIRDatabasedeveloped by RWTH Aachen University. The facial expressions present in the dataset are Fear, Anger, Contempt, Disgust, Happy, Neutral, Sad, and Surprise. The proposed model produces 88.43% recognition accuracy, better than some state-of-the-art methods considered here for comparison. Our model provides a robust framework for the detection of accurate expression in the absence of visible light.