bluuebunny/crossref_metadata_2025 huggingface dataset:
Proximity of Items Does Not Necessarily Affect Their	Correlation
Authors: Gottfried Jaroslav , Michele Lukáš , Ježek Stanislav
Published: July 2021

Abstract. In this paper, we attempted to detect the effect of provided answers on those that succeed them, the “item proximity effect,” within a questionnaire with randomized item order for each respondent. In two studies, we administered personality inventories to two samples of mostly undergraduate students, consisting of 742 and 205 respondents, respectively. We expected to see a strong item proximity effect that quickly diminishes with higher item distances, but we found no evidence of such effect in the data. Thus, we failed to conceptually replicate the findings of previous studies. After discussing the probable causes for these discrepancies, we argue that a general item proximity effect does not need to be considered a major factor when employing and evaluating common psychological inventories with randomized item order for research purposes.
Exoplanets in the Shadows
Authors: Benningfield Damond
Published: July 2021

The bright clutter of individual discoveries can overshadow some fascinating research, from necroplanetology to rogue planets to the intimacy of alphanumeric nomenclature.
Accelerated Recent Warming and Temperature Variability Over the Past Eight Centuries in the Central Asian Altai From Blue Intensity in Tree Rings
Authors: Davi N. K. , Rao M. P. , Wilson R. , Andreu‐Hayles L. , Oelkers R. , D'Arrigo R. , Nachin B. , Buckley B. , Pederson N. , Leland C. , Suran B.
Published: July 2021

Warming in Central Asia has been accelerating over the past three decades and is expected to intensify through the end of this century. Here, we develop a summer temperature reconstruction for western Mongolia spanning eight centuries (1269–2004 C.E.) using delta blue intensity measurements from annual rings of Siberian larch. A significant cooling response is observed in the year following major volcanic events and up to five years post‐eruption. Observed summer temperatures since the 1990s are the warmest over the past eight centuries, an observation that is also well captured in Coupled Model Intercomparison Project (CMIP5) climate model simulations. Projections for summer temperature relative to observations suggest further warming of between ∼3°C and 6°C by the end of the century (2075–2099 cf. 1950–2004) under the representative concentration pathways 4.5 and 8.5 (RCP4.5 and RCP8.5) emission scenarios. We conclude that projected future warming lies beyond the range of natural climate variability for the past millennium as estimated by our reconstruction.
Microphysical Origin of Raindrop Size Distributions During the Indian Monsoon
Authors: Raut Bhupendra A. , Konwar Mahen , Murugavel P. , Kadge Dhananjay , Gurnule Dinesh , Sayyed Imran , Todekar Kiran , Malap Neelam , Bankar Shivdas , Prabhakaran Thara
Published: July 2021

Surface raindrop size distributions over a rain shadow region during the Indian summer monsoon are clustered using the k‐means algorithm. The rainfall for five dominant clusters has distinct vertical features in polarimetric radar and micro rain radar. The deep convection with low cloud bases and high liquid water is associated with sharply increasing radar reflectivity at low levels and the largest drops at the surface. The large drops, originated by ice processes, break while falling below the melting layer, causing a peak in raindrops smaller than 0.5 mm diameter near the cloud base, where the falling raindrops rapidly grow by collision‐coalescence without breaking. The number concentration in the stratiform rain is relatively moderate; hence a gradual raindrop growth, and uniform vertical reflectivity. However, few raindrops in stratiform rain grow to a larger diameter than in convective rain, for the same rain rate due to the absence of collisional breakup.
Magnetotactic Bacterial Activity in the North Pacific Ocean and Its Relationship to Asian Dust Inputs and Primary Productivity Since 8.0 Ma
Authors: Zhang Qiang , Liu Qingsong , Roberts Andrew P. , Yu Jimin , Liu Yan , Li Jinhua
Published: July 2021

Magnetotactic bacteria (MTB) require iron and organic carbon for biomineralization, which can be supplied by dust inputs that stimulate primary productivity in iron‐limited oceans. However, MTB activity and its relationship to Asian dust inputs and primary productivity are not well known in the North Pacific Ocean. Here, we present an eight‐million‐year record of magnetofossil abundance, Asian dust flux, and primary productivity from North Pacific sediments (Ocean Drilling Program Hole 885A). Our results demonstrate that Asian dust delivered iron to stimulate primary productivity and then boost MTB biomineralization in the late Miocene. Since the late Pliocene, dust inputs and primary productivity appear to have been decoupled, with MTB activity controlled mainly by primary productivity rather than dust inputs. Equant magnetofossil abundances co‐vary with eolian flux, and may provide here a proxy for dust inputs. This work provides perspectives on relationship between MTB activity, dust inputs, and primary productivity on million‐year timescales.
Draining the Landscape: How Do Nitrogen Concentrations in Riparian Groundwater and Stream Water Change Following Milldam Removal?
Authors: Lewis Evan , Inamdar Shreeram , Gold Arthur J. , Addy Kelly , Trammell Tara L. E. , Merritts Dorothy , Peipoch Marc , Groffman Peter M. , Hripto Johanna , Sherman Melissa , Kan Jinjun , Walter Robert , Peck Erin
Published: July 2021

Dam removals are on the increase across the US with Pennsylvania currently leading the nation. While most dam removals are driven by aquatic habitat and public safety considerations, we know little about how dam removals impact water quality and riparian zone processes. Dam removals decrease the stream base level, which results in dewatering of the riparian zone. We hypothesized that this dewatering of the riparian zone would increase nitrification and decrease denitrification, and thus result in nitrogen (N) leakage from riparian zones. This hypothesis was tested for a 1.5 m high milldam removal. Stream, soil water, and groundwater N concentrations were monitored over 2 years. Soil N concentrations and process rates and δ15N values were also determined. Denitrification rates and soil δ15N values in riparian sediments decreased supporting our hypothesis but no significant changes in nitrification were observed. While surficial soil water nitrate‐N concentrations were high (median 4.5 mg N L−1), riparian groundwater nitrate‐N values were low (median 0.09 mg N L−1), indicating that nitrate‐N leakage was minimal. We attribute the low groundwater nitrate‐N to denitrification losses at the lower, more dynamic, groundwater interface and/or dissimilatory nitrate reduction to ammonium (DNRA). Stream water nitrate‐N concentrations were high (median 7.6 mg N L−1) and contrary to our dam‐removal hypothesis displayed a watershed‐wide decline that was attributed to regional hydrologic changes. This study provided important first insights on how dam removals could affect N cycle processes in riparian zones and its implications for water quality and watershed management.
Structures and Deformation in Glaciers and Ice Sheets
Authors: Jennings Stephen J. A. , Hambrey Michael J.
Published: July 2021

The aims of this review are to: (a) describe and interpret structures in valley glaciers in relation to strain history; and (b) to explore how these structures inform our understanding of the kinematics of large ice masses, and a wide range of other aspects of glaciology. Structures in glaciers give insight as to how ice deforms at the macroscopic and larger scale. Structures also provide information concerning the deformation history of ice masses over centuries and millennia. From a geological perspective, glaciers can be considered to be models of rock deformation, but with rates of change that are measurable on a human time‐scale. However, structural assemblages in glaciers are commonly complex, and unraveling them to determine the deformation history is challenging; it thus requires the approach of the structural geologist. A wide range of structures are present in valley glaciers: (a) primary structures include sedimentary stratification and various veins; (b) secondary structures that are the result of brittle and ductile deformation include crevasses, faults, crevasse traces, foliation, folds, and boudinage structures. Some of these structures, notably crevasses, relate well to measured strain‐rates, but to explain ductile structures analysis of cumulative strain is required. Some structures occur in all glaciers irrespective of size, and they are therefore recognizable in ice streams and ice shelves. Structural approaches have wide (but as yet under‐developed potential) application to other sub‐disciplines of glaciology, notably glacier hydrology, debris entrainment and transfer, landform development, microbiological investigations, and in the interpretation of glacier‐like features on Mars.
Improved Regional Scale Dynamic Evapotranspiration Estimation Under Changing Vegetation and Climate
Authors: Giles‐Hansen Krysta , Wei Xiaohua
Published: July 2021

Vegetation change can significantly alter evapotranspiration (ET), an important component of the terrestrial water balance, and consequently influences other hydrological processes. With no direct measurement techniques available at large spatial scales, the accurate estimation of ET under changing forest landscapes and climate is challenging. In this study, we used an improved method based on Fuh's equation (a functional form of the Budyko framework) to investigate ET responses to cumulative forest disturbance and climate in the snow‐dominated interior of British Columbia, Canada. First, we divided the study region into three distinct climate groups, and then related the watershed parameter m in Fuh's equation to vegetation change (represented by cumulative equivalent clearcut area (CECA)) and watershed properties, with independent calibration and validation watersheds. The validated relationships were used to examine regional ET variations (∼380,000 km2). Our results showed that ET in moderate climates had the highest sensitivity to CECA, characterized by wetness index between 1 and 2 (the ratio of precipitation to potential evapotranspiration). ET in dry climates (wetness index <1) was also significantly related to CECA, but with reduced sensitivity compared to the moderate climates. Wetter climates (wetness index >2) did not show a significant relationship with CECA, suggesting an insensitivity of ET to forest change. Simulations under future climate and vegetation disturbance scenarios demonstrated that ET would be further decreased in most of the study region. Forest management should consider reducing disturbance in the dry to moderate climate areas to mitigate negative impacts on hydrological processes and functions.
B-Myb accelerates colorectal cancer progression through reciprocal feed-forward transactivation of E2F2
Authors: Fan Xiaoyan , Wang Yitao , Jiang Tinghui , Liu Tao , Jin Yuelei , Du Kailong , Niu Yulong , Zhang Chunxue , Liu Zhongyu , Lei Yunlong , Bu Youquan
Published: July 2021

B-Myb is an important transcription factor that plays a critical role in gene expression regulation and tumorigenesis. However, its functional implication in colorectal cancer remains elusive. In this study, we found that B-Myb was significantly upregulated at both mRNA and protein levels in colorectal cancer samples compared to non-tumor counterparts. B-Myb overexpression accelerated cell proliferation, cell cycle progression and cell motility in colorectal cancer cells, and promoted tumor growth in orthotopic nude mouse models in vivo. In contrast, B-Myb depletion inhibited these malignant phenotypes. Mechanistic investigations revealed that E2F2 was a novel transcriptional target of B-Myb and is essential to B-Myb-induced malignant phenotypes. Notably, B-Myb and E2F2 exhibited positive expression correlation, and interacted with each other in colorectal cancer cells. In addition to their autoregulatory mechanisms, B-Myb and E2F2 can also directly transactivate each other, thus constituting consolidated reciprocal feed-forward transactivation loops. Moreover, both B-Myb and E2F2 are required for the activation of ERK and AKT signaling pathways in colorectal cancer cells. Taken together, our data clarified a critical role for B-Myb in colorectal cancer and unraveled an exquisite mutual collaboration and reciprocal cross regulation between B-Myb and E2F2 that contribute to the malignant progression of human colorectal cancer.
Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma
Authors: Yeh Chi-Tai , Chen Tzu-Tao , Satriyo Pamungkas Bagus , Wang Chun-Hua , Wu Alexander T. H. , Chao Tsu-Yi , Lee Kang-Yun , Hsiao Michael , Wang Liang-Shun , Kuo Kuang-Tai
Published: July 2021

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTKpos cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTKneg cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.
Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells
Authors: Zou Zhigeng , Zheng Wei , Fan Hongjun , Deng Guodong , Lu Shih-Hsin , Jiang Wei , Yu Xiying
Published: July 2021

Background

Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood.

Methods

We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells.

Results

ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model.

Conclusions

ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.
The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging
Authors: Jiang Zhong-xin , Wang Yi-ning , Li Zi-yuan , Dai Zhi-hui , He Yi , Chu Kun , Gu Jia-yi , Ji Yi-Xuan , Sun Ning-xia , Yang Fu , Li Wen
Published: July 2021

Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3′UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.
TRIB2 desensitizes ferroptosis via βTrCP-mediated TFRC ubiquitiantion in liver cancer cells
Authors: Guo Susu , Chen Yuxin , Xue Xiangfei , Yang Yueyue , Wang Yikun , Qiu Shiyu , Cui Jiangtao , Zhang Xiao , Ma Lifang , Qiao Yongxia , Wang Jiayi
Published: July 2021

Tribbles homolog 2 (TRIB2) is known to boost liver tumorigenesis via regulating Ubiquitin (Ub) proteasome system (UPS). At least two ways are involved, i.e., acts as an adaptor protein to modulate ubiquitination functions of certain ubiquitin E3 ligases (E3s) and reduces global Ub levels via increasing the proteolysis activity of proteasome. Recently, we have identified the role of TRIB2 to relieve oxidative damage via reducing the availability of Ub that is essential for the ubiquitination and subsequent degradation of Glutathione peroxidase 4 (GPX4). Although GPX4 is a critical antioxidant factor to protect against ferroptosis, the exact evidence showing that TRIB2 desensitizes ferroptosis is lacking. Also, whether such function is via E3 remains unclear. Here, we demonstrated that deletion of TRIB2 sensitized ferroptosis via lifting labile iron in liver cancer cells. By contrast, overexpression of TRIB2 led to the opposite outcome. We further demonstrated that transferrin receptor (TFRC) was required for TRIB2 to desensitize the cells to ferroptosis. Without TFRC, the labile iron pool could not be reduced by overexpressing TRIB2. We also found that beta-transducin repeat containing E3 ubiqutin protein ligase (βTrCP) was a genuine E3 for the ubiquitination of TFRC, and TRIB2 was unable to decline labile iron level once upon βTrCP was knocked out. In addition, we confirmed that the opposite effects on ferroptosis and ferroptosis-associated lipid reactive oxygen species (ROS) generation resulted from knockout and overexpression of TRIB2 were all indispensible of TFRC and βTrCP. Finally, we demonstrated that TRIB2 exclusively manipulated RSL3- and erastin-induced-ferroptosis independent of GPX4 and glutathione (GSH). In conclusion, we elucidated a novel role of TRIB2 to desensitize ferroptosis via E3 βTrCP, by which facilitates TFRC ubiquitiation and finally decreases labile iron in liver cancer cells.
The therapeutic implications of immunosuppressive tumor aerobic glycolysis
Authors: Reinfeld Bradley I. , Rathmell W. Kimryn , Kim Tae Kon , Rathmell Jeffrey C.
Published: July 2021

In 2011, Hanahan and Weinberg added “Deregulating Cellular Energetics” and “Avoiding Immune Destruction” to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
Treatment-related amenorrhea in a modern, prospective cohort study of young women with breast cancer
Authors: Poorvu Philip D. , Hu Jiani , Zheng Yue , Gelber Shari I. , Ruddy Kathryn J. , Tamimi Rulla M. , Peppercorn Jeffrey M. , Schapira Lidia , Borges Virginia F. , Come Steven E. , Warner Ellen , Lambertini Matteo , Rosenberg Shoshana M. , Partridge Ann H.
Published: July 2021

Young women with breast cancer experience unique treatment and survivorship issues centering on treatment-related amenorrhea (TRA), including fertility preservation and management of ovarian function as endocrine therapy. The Young Women’s Breast Cancer Study (YWS) is a multi-center, prospective cohort study of women diagnosed at age ≤40, enrolled from 2006 to 2016. Menstrual outcomes were self-reported on serial surveys. We evaluated factors associated with TRA using logistic regression. One year post-diagnosis, 286/789 (36.2%) experienced TRA, yet most resumed menses (2-year TRA: 120/699; 17.2%). Features associated with 1-year TRA included older age (OR≤30vs36-40 = 0.29 (0.17–0.48), OR31-35vs36-40 = 0.67 (0.46–0.94), p = 0.02); normal body mass index (BMI) (OR≥25vs18.5-24. =0.59 (0.41–0.83), p < 0.01); chemotherapy (ORchemo vs no chemo = 5.55 (3.60–8.82), p < 0.01); and tamoxifen (OR = 1.55 (1.11–2.16), p = 0.01). TRA rates were similar across most standard regimens (docetaxel/carboplatin/trastuzumab +/− pertuzumab: 55.6%; docetaxel/cyclophosphamide +/− trastuzumab/pertuzumab: 41.8%; doxorubicin/cyclophosphamide/paclitaxel +/− trastuzumab/pertuzumab: 44.1%; but numerically lower with AC alone (25%) or paclitaxel/trastuzumab (11.1%). Among young women with breast cancer, lower BMI appears to be an independent predictor of TRA. This finding has important implications for interpretation of prior studies, future research, and patient care in our increasingly obese population. Additionally, these data describe TRA associated with use of docetaxel/cyclophosphamide, which is increasingly being used in lieu of anthracycline-containing regimens. Collectively, these data can be used to inform use of fertility preservation strategies for women who need to undergo treatment as well as the potential need for ovarian suppression following modern chemotherapy for young women with estrogen-receptor-positive breast cancer.

Clinical trial registration: www.clinicaltrials.gov, NCT01468246.
Association between genes regulating neural pathways for quantitative traits of speech and language disorders
Authors: Benchek Penelope , Igo Robert P. , Voss-Hoynes Heather , Wren Yvonne , Miller Gabrielle , Truitt Barbara , Zhang Wen , Osterman Michael , Freebairn Lisa , Tag Jessica , Taylor H. Gerry , Chan E. Ricky , Roussos Panos , Lewis Barbara , Stein Catherine M. , Iyengar Sudha K.
Published: July 2021

Speech sound disorders (SSD) manifest as difficulties in phonological memory and awareness, oral motor function, language, vocabulary, reading, and spelling. Families enriched for SSD are rare, and typically display a cluster of deficits. We conducted a genome-wide association study (GWAS) in 435 children from 148 families in the Cleveland Family Speech and Reading study (CFSRS), examining 16 variables representing 6 domains. Replication was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 18 significant loci (combined p < 10−8) that we pursued bioinformatically. We prioritized 5 novel gene regions with likely functional repercussions on neural pathways, including those which colocalized with differentially methylated regions in our sample. Polygenic risk scores for receptive language, expressive vocabulary, phonological awareness, phonological memory, spelling, and reading decoding associated with increasing clinical severity. In summary, neural-genetic influence on SSD is primarily multigenic and acts on genomic regulatory elements, similar to other neurodevelopmental disorders.
Zero gravity induced by parabolic flight enhances automatic capture and weakens voluntary maintenance of visuospatial attention
Authors: Salatino Adriana , Iacono Claudio , Gammeri Roberto , Chiadò Stefano T. , Lambert Julien , Sulcova Dominika , Mouraux André , George Mark S. , Roberts Donna R. , Berti Anna , Ricci Raffaella
Published: July 2021

Orienting attention in the space around us is a fundamental prerequisite for willed actions. On Earth, at 1 g, orienting attention requires the integration of vestibular signals and vision, although the specific vestibular contribution to voluntary and automatic components of visuospatial attention remains largely unknown. Here, we show that unweighting of the otolith organ in zero gravity during parabolic flight, selectively enhances stimulus-driven capture of automatic visuospatial attention, while weakening voluntary maintenance of covert attention. These findings, besides advancing our comprehension of the basic influence of the vestibular function on voluntary and automatic components of visuospatial attention, may have operational implications for the identification of effective countermeasures to be applied in forthcoming human deep space exploration and habitation, and on Earth, for patients’ rehabilitation.
Factors influencing SARS-CoV-2 transmission and outbreak control measures in densely populated settings
Authors: Pung Rachael , Lin Bernard , Maurer-Stroh Sebastian , Sirota Fernanda L. , Mak Tze Minn , Octavia Sophie , Pang Junxiong , Tan Iain Beehuat , Tan Clive , Ong Biauw Chi , Cook Alex R. ,   The Singapore COVID-19 Outbreak Research Team, Tan Doreen , Chua Qin Xuan , Chong Samuel Zeng Rong , Koh Han Fang , Yap Elena , Sia Priscilla , Tan Ze Ren , Lee Fong Sin , Goh Jun Kang Enan , Suor Peou Socheata Monica , Ang Julian Xiao Li , Lee Vernon J.
Published: July 2021

Starting with a handful of SARS-CoV-2 infections in dormitory residents in late March 2020, rapid transmission in their dense living environments ensued and by October 2020, more than 50,000 acute infections were identified across various dormitories in Singapore. The aim of the study is to identify combination of factors facilitating SARS-CoV-2 transmission and the impact of control measures in a dormitory through extensive epidemiological, serological and phylogenetic investigations, supported by simulation models. Our findings showed that asymptomatic cases and symptomatic cases who did not seek medical attention were major drivers of the outbreak. Furthermore, each resident had about 30 close contacts and each infected resident spread to 4.4 (IQR 3.5–5.3) others at the start of the outbreak. The final attack rate of the current outbreak was 76.2% (IQR 70.6–98.0%) and could be reduced by further 10% under a modified dormitory housing condition. These findings are important when designing living environments in a post COVID-19 future to reduce disease spread and facilitate rapid implementation of outbreak control measures.
Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis
Authors: AuYeung Amanda W. K. , Mould Robert C. , Stegelmeier Ashley A. , van Vloten Jacob P. , Karimi Khalil , Woods J. Paul , Petrik James J. , Wood Geoffrey A. , Bridle Byram W.
Published: July 2021

Vaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.
Differential prioritization of intramaze cue and boundary information during spatial navigation across the human lifespan
Authors: Glöckner Franka , Schuck Nicolas W. , Li Shu-Chen
Published: July 2021

Spatial learning can be based on intramaze cues and environmental boundaries. These processes are predominantly subserved by striatal- and hippocampal-dependent circuitries, respectively. Maturation and aging processes in these brain regions may affect lifespan differences in their contributions to spatial learning. We independently manipulated an intramaze cue or the environment’s boundary in a navigation task in 27 younger children (6–8 years), 30 older children (10–13 years), 29 adolescents (15–17 years), 29 younger adults (20–35 years) and 26 older adults (65–80 years) to investigate lifespan age differences in the relative prioritization of either information. Whereas learning based on an intramaze cue showed earlier maturation during the progression from younger to later childhood and remained relatively stable across adulthood, maturation of boundary-based learning was more protracted towards peri-adolescence and showed strong aging-related decline. Furthermore, individual differences in prioritizing intramaze cue- over computationally more demanding boundary-based learning was positively associated with cognitive processing fluctuations and this association was partially mediated by spatial working memory capacity during adult, but not during child development. This evidence reveals different age gradients of two modes of spatial learning across the lifespan, which seem further influenced by individual differences in cognitive processing fluctuations and working memory, particularly during aging.
Biocementation mediated by native microbes from Brahmaputra riverbank for mitigation of soil erodibility
Authors: Dubey Anant Aishwarya , Ravi K. , Mukherjee Abhijit , Sahoo Lingaraj , Abiala Moses Akindele , Dhami Navdeep K.
Published: July 2021

Riverbank erosion is a global problem with significant socio-economic impacts. Microbially induced calcite precipitation (MICP) has recently emerged as a promising technology for improving the mechanical properties of soils. The present study investigates the potential of selectively enriched native calcifying bacterial community and its supplementation into the riverbank soil of the Brahmaputra river for reducing the erodibility of the soil. The ureolytic and calcium carbonate cementation abilities of the enriched cultures were investigated with reference to the standard calcifying culture of Sporosarcina pasteurii (ATCC 11859). 16S rRNA analysis revealed Firmicutes to be the most predominant calcifying class with Sporosarcina pasteurii and Pseudogracilibacillus auburnensis as the prevalent strains. The morphological and mineralogical characterization of carbonate crystals confirmed the calcite precipitation potential of these communities. The erodibility of soil treated with native calcifying communities was examined via needle penetration and lab-scale hydraulic flume test. We found a substantial reduction in soil erosion in the biocemented sample with a calcite content of 7.3% and needle penetration index of 16 N/mm. We report the cementation potential of biostimulated ureolytic cultures for minimum intervention to riparian biodiversity for an environmentally conscious alternative to current erosion mitigation practices.
Country transition index based on hierarchical clustering to predict next COVID-19 waves
Authors: Rios Ricardo A. , Nogueira Tatiane , Coimbra Danilo B. , Lopes Tiago J. S. , Abraham Ajith , Mello Rodrigo F. de
Published: July 2021

COVID-19 has widely spread around the world, impacting the health systems of several countries in addition to the collateral damage that societies will face in the next years. Although the comparison between countries is essential for controlling this disease, the main challenge is the fact of countries are not simultaneously affected by the virus. Therefore, from the COVID-19 dataset by the Johns Hopkins University Center for Systems Science and Engineering, we present a temporal analysis on the number of new cases and deaths among countries using artificial intelligence. Our approach incrementally models the cases using a hierarchical clustering that emphasizes country transitions between infection groups over time. Then, one can compare the current situation of a country against others that have already faced previous waves. By using our approach, we designed a transition index to estimate the most probable countries’ movements between infectious groups to predict next wave trends. We draw two important conclusions: (1) we show the historical infection path taken by specific countries and emphasize changing points that occur when countries move between clusters with small, medium, or large number of cases; (2) we estimate new waves for specific countries using the transition index.
Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin
Authors: Lauer Anna A. , Janitschke Daniel , dos Santos Guilherme Malena , Nguyen Vu Thu Thuy , Bachmann Cornel M. , Qiao Sen , Schrul Bianca , Boehm Ulrich , Grimm Heike S. , Hartmann Tobias , Endres Kristina , Grimm Marcus O. W.
Published: July 2021

Alzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris,
increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.
Elevated plasma miR-133b and miR-221-3p as biomarkers for early Parkinson’s disease
Authors: Chen Qihua , Deng Na , Lu Ke , Liao Qiao , Long Xiaoyan , Gou Deming , Bi Fangfang , Zhou Jinxia
Published: July 2021

Blood circulating microRNAs (miRNAs) are proposed to be promising biomarkers for many neurodegenerative disorders, including Parkinson’s disease (PD). However, there is a lack of identified differentially expressed miRNAs in PD from different studies. The aim of this study was to evaluate miRNAs expression in PD. We measured plasma circulating miRNA expression in three independent sets with a total of 151 PD patients, 21 multiple system atrophy (MSA) patients and 138 healthy controls using high-throughput RT-PCR. We identified that elevated miR-133b and miR-221-3p discriminated early-stage PD from controls with 94.4% sensitivity and 91.1% specificity. Elevated miR-133b and miR-221-3p distinguished PD from controls with 84.8% sensitivity and 88.9% specificity. In addition, miR-4454 distinguished PD from MSA with 57.1% sensitivity and 82.6% specificity. Hence, elevated miR-133b and miR-221-3p potentially represent good biomarkers for early PD, and a combination of miR-133b, miR-221-3p and miR-4454 has the potential to serve as a non-invasive biomarker for PD diagnosis.
Impacts of treatments on recurrence and 28-year survival of ischemic stroke patients
Authors: Wang Ting-Ann , Wu Tzy-Haw , Pan Shin-Liang , Chen Hsiu-Hsi , Chiu Sherry Yueh-Hsia
Published: July 2021

Aspirin and nicametate are well-established therapies for preventing recurrence and mortality from stroke in patients diagnosed as ischemic stroke. However, their respective effects on the recurrence, making allowance for the duration of recurrence and death without the occurrence of recurrence, and long-term survival have not been well elucidated. We aimed to evaluate long-term effect of two kinds of treatment on cerebrovascular death among ischemic stroke patients with or without the recurrence of stroke. Data used in this study were derived from the cohort based on a multicenter randomized double-blind controlled trial during 1992 to 1995 with the enrollment of a total of 466 patients with first-time non-cardioembolic ischemic stroke who were randomly allocated to receive aspirin (n = 222) or nicametate (n = 244). The trial cohort was followed up over time to ascertain the date of recurrence within trial period and death until Sep of 2019. The time-dependent Cox regression model was used to estimate the long-term effects of two treatments on death from cerebrovascular disease with and without recurrence. A total of 49 patients experienced stroke recurrence and 89 cerebrovascular deaths was confirmed. Patients treated with nicametate were more likely, but non statistically significantly, to have recurrence (aHR: 1.73, 95% CI 0.96–3.13) as compared with those treated by aspirin. Nicametate reduced the risk of cerebrovascular death about 37% (aHR: 0.63, 95% CI 0.41–0.97) compared with aspirin. The aspirin group had a lower recurrence rate than the nicametate group even with recurrence after 1–2 years of follow-up of first stroke but the latter had significantly reduced death from cerebrovascular disease for nicametate group, which requires more research to verify.
Association between statin use and Alzheimer’s disease with dose response relationship
Authors: Jeong Su-Min , Shin Dong Wook , Yoo Tae Gon , Cho Mi Hee , Jang Wooyoung , Lee Jinkook , Kim SangYun
Published: July 2021

This study aimed to determine the dose–response relationship between the levels of statin exposure and the incidence of Alzheimer’s disease (AD). We included 119,013 Korean adults (≥ 60 years old) using a database from the Korean National Health Insurance Service (2002–2013). Statin exposure was treated as a time-varying variable. Incidence of AD was defined by the first claim code for AD with anti-Alzheimer drugs. AD occurred in 9467 cases during a median 7.2 years of follow-up. Overall, statin use was not associated with an increased risk of AD incidence [adjusted hazard ratio (aHR) = 1.04; 95% confidence interval (CI) = 0.99–1.10]. When examined by level of statin exposure, statin prescription < 540 days during a 2-year window time was associated with a higher risk for incidence of AD compared to statin non-use. However, days of prescription ≥ 540 and cumulative defined daily dose ≥ 540 of statin were associated with decreased risk of AD [aHR (95% CI) = 0.87 (0.80–0.95) and 0.79 (0.68–0.92), respectively]. Our findings indicate that less persistent statin use is associated with increased risk of AD, whereas persistent and adherent statin use is associated with decreased risk of AD.
Calcium functional imaging with high-resolution CT in the inner ear
Authors: Tanioka Hisaya , Tanioka Sayaka
Published: July 2021

Although the otolith and otolith organs correlate with vertigo and instability, there is no method to investigate them without harmful procedures. We will create the technique for 3D microanatomical images of them, and investigate the in vivo internal state and metabolisms. The otolith and otolith organs images were reconstructed from a texture synthesis algorithm under the skull volume rendering algorithm using a cutting-plane method. The utricular macula was elongated pea-shaped. The saccular macula was almost bud-shaped. The changes in the amount of CaCO3 in the maculae and the endolymphatic sac showed various morphologies, reflecting the balance status of each subject. Both shapes and volumes were not always constant depending on time. In Meniere’s disease (MD), the saccular macula was larger and the utricular macula was smaller. In benign paroxysmal positional vertigo (BPPV), the otolith increased in the utricular macula but did not change much in the saccular macula. The saccule, utricle, and endolymphatic sac were not constantly shaped according to their conditions. These created 3D microanatomical images can allow detailed observations of changes in physiological and biological information. This imaging technique will contribute to our understanding of pathology and calcium metabolism in the in vivo vestibulum.
Impact of endoscopic submucosal dissection and epithelial cell sheet engraftment on systemic cytokine dynamics in patients with oesophageal cancer
Authors: Yoshida Akira , Takata Tomoaki , Kanda Tsutomu , Yamaguchi Naoyuki , Minami Hitomi , Nakao Kazuhiko , Kobayashi Shinichiro , Eguchi Susumu , Isomoto Hajime
Published: July 2021

The tumour microenvironment (TME) plays an important role in cancer development, progression, and metastasis. Various cytokines are present in the TME in oesophageal cancer. Oesophageal stricture is a major complication of endoscopic submucosal dissection (ESD) for oesophageal cancer, and inflammatory cytokines are closely related to its pathogenesis. However, the cytokine crosstalk involved in the oesophageal cancer TME and post-ESD stricture has not been fully elucidated. This study investigated the comprehensive cytokine dynamics following ESD in patients with oesophageal cancer. In addition, the effect of a novel preventive technique for post-ESD stricture, autologous cell sheet engraftment, on cytokine levels was evaluated. Various pro-inflammatory and anti-tumorigenic cytokines were elevated in patients with oesophageal cancer, and ESD transiently influenced cytokine concentrations. IL-1β and TNF-α, two major pro-inflammatory cytokines that induce oesophageal stricture, were significantly suppressed by cell sheet engraftment. In conclusion, this study revealed the distinct cytokine dynamics after ESD in patients with oesophageal cancer, together with the effect of autologous cell sheet engraftment on cytokine fluctuation. These results can accelerate research on the TME and therapeutic strategies for oesophageal cancer.
Inter-eye genomic heterogeneity in bilateral retinoblastoma via aqueous humor liquid biopsy
Authors: Wong Elyssa Y. , Xu Liya , Shen Lishuang , Kim Mary E. , Polski Ashley , Prabakar Rishvanth K. , Shah Rachana , Jubran Rima , Kim Jonathan W. , Biegel Jaclyn A. , Gai Xiaowu , Kuhn Peter , Hicks James , Berry Jesse L.
Published: July 2021

Germline alterations in the RB1 tumor suppressor gene predispose patients to develop retinoblastoma (RB) in both eyes. While similar treatment is given for each eye, there is often a variable therapeutic response between the eyes. Herein, we use the aqueous humor (AH) liquid biopsy to evaluate the cell-free tumor DNA (ctDNA) from each eye in a patient with bilateral RB. Despite the same predisposing germline RB1 mutation, AH analysis identified a different somatic RB1 mutation as well as separate and distinct chromosomal alterations in each eye. The longitudinal alterations in tumor fraction (TFx) corresponded to therapeutic responses in each eye. This case demonstrates that bilateral RB tumors develop separate genomic alterations, which may play a role in tumorigenesis and prognosis for eye salvage. Identifying these inter-eye differences without the need for enucleated tumor tissue may help direct active management of RB, with particular usefulness in bilateral cases.
Multicomponent and multisensory communicative acts in orang-utans may serve different functions
Authors: Fröhlich Marlen , Bartolotta Natasha , Fryns Caroline , Wagner Colin , Momon Laurene , Jaffrezic Marvin , Mitra Setia Tatang , van Noordwijk Maria A. , van Schaik Carel P.
Published: July 2021

From early infancy, human face-to-face communication is multimodal, comprising a plethora of interlinked communicative and sensory modalities. Although there is also growing evidence for this in nonhuman primates, previous research rarely disentangled production from perception of signals. Consequently, the functions of integrating articulators (i.e. production organs involved in multicomponent acts) and sensory channels (i.e. modalities involved in multisensory acts) remain poorly understood. Here, we studied close-range social interactions within and beyond mother-infant pairs of Bornean and Sumatran orang-utans living in wild and captive settings, to examine use of and responses to multicomponent and multisensory communication. From the perspective of production, results showed that multicomponent acts were used more than the respective unicomponent acts when the presumed goal did not match the dominant outcome for a specific communicative act, and were more common among non-mother-infant dyads and Sumatran orang-utans. From the perception perspective, we found that multisensory acts were more effective than the respective unisensory acts, and were used more in wild compared to captive populations. We argue that multisensory acts primarily facilitate effectiveness, whereas multicomponent acts become relevant when interaction outcomes are less predictable. These different functions underscore the importance of distinguishing between production and perception in studies of communication.