bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of novel heat shock-induced long non-coding RNA in human cells
Authors: Onoguchi-Mizutani Rena , Kishi Yoshihiro , Ogura Yoko , Nishimura Yuuki , Imamachi Naoto , Suzuki Yutaka , Miyazaki Satoru , Akimitsu Nobuyoshi
Published: October 2020

The heat-shock response is a crucial system for survival of organisms under heat stress. During heat-shock stress, gene expression is globally suppressed, but expression of some genes, such as chaperone genes, is selectively promoted. These selectively activated genes have critical roles in the heat-shock response, so it is necessary to discover heat-inducible genes to reveal the overall heat-shock response picture. The expression profiling of heat-inducible protein-coding genes has been well-studied, but that of non-coding genes remains unclear in mammalian systems. Here, we used RNA-seq analysis of heat shock-treated A549 cells to identify seven novel long non-coding RNAs that responded to heat shock. We focussed on CTD-2377D24.6 RNA, which is most significantly induced by heat shock, and found that the promoter region of CTD-2377D24.6 contains the binding site for transcription factor HSF1 (heat shock factor 1), which plays a central role in the heat-shock response. We confirmed that HSF1 knockdown cancelled the induction of CTD-2377D24.6 RNA upon heat shock. These results suggest that CTD-2377D24.6 RNA is a novel heat shock-inducible transcript that is transcribed by HSF1.
Status Pivoting
Authors: Goor Dafna , Keinan Anat , Ordabayeva Nailya
Published: October 2020

Prior research has established that status threat leads consumers to display status-related products such as luxury brands. While compensatory consumption within the domain of the status threat (e.g., products associated with financial and professional success) is the most straightforward way to cope with comparisons to high-status individuals, we examine when, why, and how consumers cope with status threat by choosing to “pivot” and display success and achievements in alternative domains. Using a mixed-method approach combining field and lab experiments, incentive-compatible designs, netnographic analysis, observational study, and qualitative interviews, we show that consumers cope with status threat by signaling their status and success in alternative domains. We conceptualize this behavior as “status pivoting” and show that it occurs because experiencing status threat motivates consumers to adopt beliefs about tradeoffs across domains; that is, to believe that status acquisition requires tradeoffs and hence others’ success in one domain comes at the cost of success in another domain. We compare the prevalence and appeal of status pivoting to restoring status within the domain of the threat. We further examine when consumers are likely to engage in status pivoting and show that this effect is attenuated when high status within the domain of the threat is attainable.
Banks Grass Mite (Acari: Tetranychidae) Suppression May Add to the Benefit of Drought-Tolerant Corn Hybrids Exposed to Water Stress
Authors: Ruckert Alice , Golec Julian R , Barnes Cody L , Ramirez Ricardo A
Published: October 2020

Spider mite (Acari: Tetranychidae) outbreaks are common on corn grown in the arid West. Hot and dry conditions reduce mite development time, increase fecundity, and accelerate egg hatch. Climate change is predicted to increase drought incidents and produce more intense temperature patterns. Together, these environmental shifts may cause more frequent and severe spider mite infestations. Spider mite management is difficult as many commercially available acaricides are ineffective due to the development of resistance traits in field mite populations. Therefore, alternative approaches to suppress outbreaks are critically needed. Drought-tolerant plant hybrids alleviate the challenges of growing crops in water-limited environments; yet, it is unclear if drought-tolerant hybrids exposed to water stress affect mite outbreaks under these conditions. We conducted a greenhouse experiment to evaluate the effect of drought-tolerant corn hybrids on Banks grass mite [Oligonychus pratensis Banks (Acari: Tetranychidae)], a primary pest of corn, under optimal irrigation and water-stress irrigation. This was followed by a 2-yr field study investigating the effect of drought-tolerant corn hybrids exposed to the same irrigation treatments on Banks grass mite artificially infested on hybrids and resident spider mite populations. Results showed that water-stressed drought-tolerant hybrids had significantly lower Banks grass mite and resident spider mite populations than water-stressed drought-susceptible hybrids. Interestingly, water-stressed drought-tolerant hybrids had equal Banks grass mite populations to drought-susceptible and drought-tolerant hybrids under optimal irrigation. We posit that planting drought-tolerant hybrids may suppress spider mite outbreaks in water-challenged areas.
Immunotherapy for advanced melanoma: current situation in Japan
Authors: Kato Junji , Uhara Hisashi
Published: October 2020

Treatment with immune checkpoint inhibitors provides long-term survival for patients with advanced melanoma. Improvements in the overall survival of advanced melanoma patients have been achieved with anti-PD-1 monotherapy and anti-PD-1+ CTLA4 combination therapy, but there are still many issues to resolve. Acral, mucosal and uveal melanoma have been less responsive to immune checkpoint inhibitors than cutaneous melanoma. For patients who have achieved a good response, it is still not known how long the anti-PD-1 therapy should be administered. Moreover, there is limited treatment for patients who relapse during or after adjuvant anti-PD-1 therapy. Here, we review the current evidence regarding the clinical effects of immunotherapy for advanced melanoma. Moreover, we review previous studies of acral, mucosal and uveal melanoma, and we discuss the recent findings regarding durable response after the cessation of anti-PD-1 therapy, and treatment options for recurrence after adjuvant therapy.
Syzygium samarangense Leaf Infusion as Aedes albopictus (Diptera: Culicidae) Ovitrap Bait
Authors: Shu Ching-Yu , Shelomi Matan
Published: October 2020

Adding lures can improve the efficiency of mosquito ovitraps used for monitoring or in attract-and-kill pest management. Easily produced, low-to-no cost bait would be ideal for remote field sites and community-run vector management. Plant infusions are popular ovitrap baits for their low cost and potent attractiveness, attributed either to the plants or their microbiomes. We tested fermented leaf infusions of the wax apple tree, Syzygium samarangense (Blume) Merr. & Perry, as bait in lethal ovitraps in urban Taipei with Bti larvicide. All trapped insects were inferred to be Asian tiger mosquito, Aedes albopictus (Skuse). The bait significantly increased the yield of the traps, with no negative interactions with the larvicide in either direction. Syzgium samarangense leaves are readily available across Taiwan, making their infusion an easy bait to greatly improve ovitrap efficiency.
Effect of 10-Valent Pneumococcal Conjugate Vaccine on Streptococcus pneumoniae Nasopharyngeal Carriage Among Children Less Than 5 Years Old: 3 Years Post-10-Valent Pneumococcal Conjugate Vaccine Introduction in Mozambique
Authors: Valenciano Sandra J , Moiane Benild , Lessa Fernanda C , Chaúque Alberto , Massora Sergio , Pimenta Fabiana C , Mucavele Helio , Verani Jennifer R , da Gloria Carvalho Maria , Whitney Cynthia G , Tembe Nelson , Sigaúque Betuel
Published: October 2020

Background

Mozambique introduced 10-valent pneumococcal conjugate vaccine (PCV10) in 2013 with doses at ages 2, 3, and 4 months and no catch-up or booster dose. We evaluated PCV10 impact on the carriage of vaccine-type (VT), non-VT, and antimicrobial non-susceptible pneumococci 3 years after introduction.

Methods

We conducted cross-sectional carriage surveys among HIV-infected and HIV-uninfected children aged 6 weeks to 59 months: 1 pre-PCV10 (2012–2013 [Baseline]) and 2 post-PCV10 introductions (2014–2015 [Post1] and 2015–2016 [Post2]). Pneumococci isolated from nasopharyngeal swabs underwent Quellung serotyping and antimicrobial susceptibility testing. Non-susceptible isolates (intermediate or resistant) were defined using Clinical and Laboratory Standards Institute 2018 breakpoints. We used log-binomial regression to estimate changes in the pneumococcal carriage between survey periods. We compared proportions of non-susceptible pneumococci between Baseline and Post2.

Results

We enrolled 720 children at Baseline, 911 at Post1, and 1208 at Post2. Baseline VT carriage was similar for HIV-uninfected (36.0%, 110/306) and HIV-infected children (34.8%, 144/414). VT carriage was 36% (95% confidence interval [CI]: 19%–49%) and 27% (95% CI: 11%–41%) lower in Post1 vs baseline among HIV-uninfected and HIV-infected children, respectively. VT carriage prevalence declined in Post2 vs Post1 for HIV-uninfected but remained stable for HIV-infected children. VT carriage prevalence 3 years after PCV10 introduction was 14.5% in HIV-uninfected and 21.0% in HIV-infected children. Pneumococcal isolates non-susceptible to penicillin declined from 66.0% to 56.2% (P= .0281) among HIV-infected children.

Conclusions

VT and antimicrobial non-susceptible pneumococci carriage dropped after PCV10 introduction, especially in HIV-uninfected children. However, VT carriage remained common, indicating ongoing VT pneumococci transmission.
The transcription factor ZmNAC49 reduces stomatal density and improves drought tolerance in maize
Authors: Xiang Yang , Sun Xiujuan , Bian Xiangli , Wei Tianhui , Han Tong , Yan Jingwei , Zhang Aying
Published: October 2020

Drought stress severely limits the growth, development, and productivity of crops, and therefore understanding the mechanisms by which plants respond to drought is crucial. In this study, we cloned a maize NAC transcription factor, ZmNAC49, and identified its function in response to drought stress. We found that ZmNAC49 is localized in the nucleus and has transcriptional activation activity. ZmNAC49 expression is rapidly and strongly induced by drought stress, and overexpression enhances stress tolerance in maize. Overexpression also significant decreases the transpiration rate, stomatal conductance, and stomatal density in maize. Detailed study showed that ZmNAC49 overexpression affects the expression of genes related to stomatal development, namely ZmTMM, ZmSDD1, ZmMUTE, and ZmFAMA. In addition, we found that ZmNAC49 can directly bind to the promoter of ZmMUTE and suppress its expression. Taken together, our results show that the transcription factor ZmNAC49 represses ZmMUTE expression, reduces stomatal density, and thereby enhances drought tolerance in maize.
Multifaceted roles of nitric oxide in tomato fruit ripening: NO-induced metabolic rewiring and consequences for fruit quality traits
Authors: Zuccarelli Rafael , Rodríguez-Ruiz Marta , Lopes-Oliveira Patrícia J , Pascoal Grazieli B , Andrade Sónia C S , Furlan Cláudia M , Purgatto Eduardo , Palma José M , Corpas Francisco J , Rossi Magdalena , Freschi Luciano
Published: October 2020

Nitric oxide (NO) has been implicated as part of the ripening regulatory network in fleshy fruits. However, very little is known about the simultaneous action of NO on the network of regulatory events and metabolic reactions behind ripening-related changes in fruit color, taste, aroma and nutritional value. Here, we performed an in-depth characterization of the concomitant changes in tomato (Solanum lycopersicum) fruit transcriptome and metabolome associated with the delayed-ripening phenotype caused by NO supplementation at the pre-climacteric stage. Approximately one-third of the fruit transcriptome was altered in response to NO, including a multilevel down-regulation of ripening regulatory genes, which in turn restricted the production and tissue sensitivity to ethylene. NO also repressed hydrogen peroxide-scavenging enzymes, intensifying nitro-oxidative stress and S-nitrosation and nitration events throughout ripening. Carotenoid, tocopherol, flavonoid and ascorbate biosynthesis were differentially affected by NO, resulting in overaccumulation of ascorbate (25%) and flavonoids (60%), and impaired lycopene production. In contrast, the biosynthesis of compounds related to tomato taste (sugars, organic acids, amino acids) and aroma (volatiles) was slightly affected by NO. Our findings indicate that NO triggers extensive transcriptional and metabolic rewiring at the early ripening stage, modifying tomato antioxidant composition with minimal impact on fruit taste and aroma.
Variation in LOD Across SARS-CoV-2 Assay Systems: Need for Standardization
Authors: Sohni Youvraj
Published: October 2020

Multiple SARS-CoV-2 emergency use authorization (EUA) tests are being used for clinical testing across various clinical testing laboratories for meeting the diagnostic challenges of the ongoing pandemic. However, cross-assay variations in performance characteristics need to be recognized. A better understanding is needed of the clinical implications of cross-assay variation in performance characteristics, particularly in the limit of detection (LOD) of the SARS-CoV-2 assays used for clinical testing. Herein, a snapshot of the diversity of SARS-CoV-2 EUA analytical assay systems including methodologies, assay designs, and technology platforms is presented. Factors affecting the variations in LOD are discussed. Potential measures that may standardize across the various assay systems are suggested. Development of international standards and reference materials for the establishment of performance characteristics may substantially alleviate potential clinical decision-making challenges. Finally, cross-assay variation in LODs among the diverse SARS-CoV-2 diagnostic assays impacts clinical decision-making with multiple assay systems in use and lack of standardization across platforms. International standards in parallel with continued cross-platform studies and collaborative efforts across pertinent healthcare entities will help mitigate some of the clinical decision-making challenges.
How biased are halo properties in cosmological simulations?
Authors: Mansfield Philip , Avestruz Camille
Published: October 2020

Cosmological N-body simulations have been a major tool of theorists for decades, yet many of the numerical issues that these simulations face are still unexplored. This paper measures numerical biases in these large, dark matter-only simulations that affect the properties of their dark matter haloes. We compare many simulation suites in order to provide several tools for simulators and analysts which help mitigate these biases. We summarize our comparisons with practical ‘convergence limits’ that can be applied to a wide range of halo properties, including halo properties which are traditionally overlooked by the testing literature. We also find that the halo properties predicted by different simulations can diverge from one another at unexpectedly high resolutions. We demonstrate that many halo properties depend strongly on force softening scale and that this dependence leads to much of the measured divergence between simulations. We offer an empirical model to estimate the impact of such effects on the rotation curves of a halo population. This model can serve as a template for future empirical models of the biases in other halo properties.
SDSS-IV MaNGA: when is morphology imprinted on galaxies?
Authors: Peterken Thomas , Merrifield Michael , Aragón-Salamanca Alfonso , Avila-Reese Vladimir , Boardman Nicholas F , Drory Niv , Lane Richard R
Published: October 2020

It remains an open question as to how long ago the morphology that we see in a present-day galaxy was typically imprinted. Studies of galaxy populations at different redshifts reveal that the balance of morphologies has changed over time, but such snapshots cannot uncover the typical time-scales over which individual galaxies undergo morphological transformation, nor which are the progenitors of today’s galaxies of different types. However, these studies also show a strong link between morphology and star formation rate (SFR) over a large range in redshift, which offers an alternative probe of morphological transformation. We therefore derive the evolution in SFR and stellar mass of a sample of 4342 galaxies in the SDSS-IV MaNGA survey through a stellar population ‘fossil record’ approach, and show that the average evolution of the population shows good agreement with known behaviour from previous studies. Although the correlation between a galaxy’s contemporaneous morphology and SFR is strong over a large range of lookback times, we find that a galaxy’s present-day morphology only correlates with its relatively recent ($\sim \! 2\, \textrm {Gyr}$) star formation history. We therefore find strong evidence that morphological transitions to galaxies’ current appearance occurred on time-scales as short as a few billion years.
Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People
Authors: Lo Yun-Hua , Cheng Hsueh-Chien , Hsiung Chia-Ni , Yang Show-Ling , Wang Han-Yu , Peng Chia-Wei , Chen Chun-Yu , Lin Kung-Ping , Kang Mei-Ling , Chen Chien-Hsiun , Chu Hou-Wei , Lin Chiao-Feng , Lee Mei-Hsuan , Liu Quintin , Satta Yoko , Lin Cheng-Jui , Lin Marie , Chaw Shu-Miaw , Loo Jun-Hun , Shen Chen-Yang , Ko Wen-Ya
Published: October 2020

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.
Antibiotic Treatment Regimes as a Driver of the Global Population Dynamics of a Major Gonorrhea Lineage
Authors: Osnes Magnus N , Dorp Lucy van , Brynildsrud Ola B , Alfsnes Kristian , Schneiders Thamarai , Templeton Kate E , Yahara Koji , Balloux Francois , Caugant Dominique A , Eldholm Vegard
Published: October 2020

The Neisseria gonorrhoeae multilocus sequence type (ST) 1901 is among the lineages most commonly associated with treatment failure. Here, we analyze a global collection of ST-1901 genomes to shed light on the emergence and spread of alleles associated with reduced susceptibility to extended-spectrum cephalosporins (ESCs).

The genetic diversity of ST-1901 falls into a minor and a major clade, both of which were inferred to have originated in East Asia. The dispersal of the major clade from Asia happened in two separate waves expanding from ∼1987 and 1996, respectively. Both waves first reached North America, and from there spread to Europe and Oceania, with multiple secondary reintroductions to Asia.

The ancestor of the second wave acquired the penA 34.001 allele, which significantly reduces susceptibility to ESCs. Our results suggest that the acquisition of this allele granted the second wave a fitness advantage at a time when ESCs became the key drug class used to treat gonorrhea. Following its establishment globally, the lineage has served as a reservoir for the repeated emergence of clones fully resistant to the ESC ceftriaxone, an essential drug for effective treatment of gonorrhea.

We infer that the effective population sizes of both clades went into decline as treatment schemes shifted from fluoroquinolones via ESC monotherapy to dual therapy with ceftriaxone and azithromycin in Europe and the United States. Despite the inferred recent population size decline, the short evolutionary path from the penA 34.001 allele to alleles providing full ceftriaxone resistance is a cause of concern.
A Phylodynamic Workflow to Rapidly Gain Insights into the Dispersal History and Dynamics of SARS-CoV-2 Lineages
Authors: Dellicour Simon , Durkin Keith , Hong Samuel L , Vanmechelen Bert , Martí-Carreras Joan , Gill Mandev S , Meex Cécile , Bontems Sébastien , André Emmanuel , Gilbert Marius , Walker Conor , Maio Nicola De , Faria Nuno R , Hadfield James , Hayette Marie-Pierre , Bours Vincent , Wawina-Bokalanga Tony , Artesi Maria , Baele Guy , Maes Piet
Published: October 2020

Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of SARS-CoV-2 have been generated and shared with the scientific community. The unparalleled volume of available genetic data presents a unique opportunity to gain real-time insights into the virus transmission during the pandemic, but also a daunting computational hurdle if analyzed with gold-standard phylogeographic approaches. To tackle this practical limitation, we here describe and apply a rapid analytical pipeline to analyze the spatiotemporal dispersal history and dynamics of SARS-CoV-2 lineages. As a proof of concept, we focus on the Belgian epidemic, which has had one of the highest spatial densities of available SARS-CoV-2 genomes. Our pipeline has the potential to be quickly applied to other countries or regions, with key benefits in complementing epidemiological analyses in assessing the impact of intervention measures or their progressive easement.
Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism
Authors: Chong Stephen Jun Fei , Iskandar Kartini , Lai Jolin Xiao Hui , Qu Jianhua , Raman Deepika , Valentin Rebecca , Herbaux Charles , Collins Mary , Low Ivan Cherh Chiet , Loh Thomas , Davids Matthew , Pervaiz Shazib
Published: October 2020

Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.
Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections
Authors: Gödecke Natascha , Riedel Jan , Herrmann Sabrina , Behme Sara , Rand Ulfert , Kubsch Tobias , Cicin-Sain Luka , Hauser Hansjörg , Köster Mario , Wirth Dagmar
Published: October 2020

Mammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained—but optionally de-activatable—expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.
Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment
Authors: Miyai Masafumi , Kanayama Tomohiro , Hyodo Fuminori , Kinoshita Takamasa , Ishihara Takuma , Okada Hideshi , Suzuki Hiroki , Takashima Shigeo , Wu Zhiliang , Hatano Yuichiro , Egashira Yusuke , Enomoto Yukiko , Nakayama Noriyuki , Soeda Akio , Yano Hirohito , Hirata Akihiro , Niwa Masayuki , Sugie Shigeyuki , Mori Takashi , Maekawa Yoichi , Iwama Toru , Matsuo Masayuki , Hara Akira , Tomita Hiroyuki
Published: October 2020

Background

Gliomas typically escape surgical resection and recur due to their “diffuse invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the “diffuse invasion” phenotype, designated the Scherer’s secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown.

Methods

We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients.

Results

Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients.

Conclusions

Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
BSR guideline on the management of adults with systemic lupus erythematosus (SLE) 2018: baseline multi-centre audit in the UK
Authors: Pearce Fiona A , Rutter Megan , Sandhu Ravinder , Batten Rebecca L , Garner Rozeena , Little Jayne , Narayan Nehal , Sharp Charlotte A , Bruce Ian N , Erb Nicola , Griffiths Bridget , Guest Hannah , Macphie Elizabeth , Packham Jon , Hiley Chris , Obrenovic Karen , Rivett Ali , Gordon Caroline , Lanyon Peter C
Published: October 2020

Objectives

To assess the baseline care provided to patients with SLE attending UK Rheumatology units, audited against standards derived from the recently published BSR guideline for the management of adults with SLE, the NICE technology appraisal for belimumab, and NHS England’s clinical commissioning policy for rituximab.

Methods

SLE cases attending outpatient clinics during any 4-week period between February and June 2018 were retrospectively audited to assess care at the preceding visit. The effect of clinical environment (general vs dedicated CTD/vasculitis clinic and specialized vs non-specialized centre) were tested. Bonferroni’s correction was applied to the significance level.

Results

Fifty-one units participated. We audited 1021 episodes of care in 1003 patients (median age 48 years, 74% diagnosed >5 years ago). Despite this disease duration, 286 (28.5%) patients had active disease. Overall in 497 (49%) clinic visits, it was recorded that the patient was receiving prednisolone, including in 28.5% of visits where disease was assessed as inactive. Low documented compliance (<60% clinic visits) was identified for audit standards relating to formal disease-activity assessment, reduction of drug-related toxicity and protection against comorbidities and damage. Compared with general clinics, dedicated clinics had higher compliance with standards for appropriate urine protein quantification (85.1% vs 78.1%, P ≤ 0.001). Specialized centres had higher compliance with BILAG Biologics Register recruitment (89.4% vs 44.4%, P ≤ 0.001) and blood pressure recording (95.3% vs 84.1%).

Conclusions

This audit highlights significant unmet need for better disease control and reduction in corticosteroid toxicity and is an opportunity to improve compliance with national guidelines. Higher performance with nephritis screening in dedicated clinics supports wider adoption of this service-delivery model.
Sleep and high-risk behavior in military service members: a mega-analysis of four diverse U.S. Army units
Authors: Mantua Janna , Bessey Alexxa F , Mickelson Carolyn A , Choynowski Jake J , Noble Jeremy J , Burke Tina M , McKeon Ashlee B , Sowden Walter J
Published: October 2020

Experimental sleep restriction and deprivation lead to risky decision-making. Further, in naturalistic settings, short sleep duration and poor sleep quality have been linked to real-world high-risk behaviors (HRB), such as reckless driving or substance use. Military populations, in general, tend to sleep less and have poorer sleep quality than nonmilitary populations due to a number of occupational, cultural, and psychosocial factors (e.g. continuous operations, stress, and trauma). Consequently, it is possible that insufficient sleep in this population is linked to HRB. To investigate this question, we combined data from four diverse United States Army samples and conducted a mega-analysis by aggregating raw, individual-level data (n = 2,296, age 24.7 ± 5.3). A negative binomial regression and a logistic regression were used to determine whether subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI], Insomnia Severity Index [ISI], and duration [h]) predicted instances of military-specific HRB and the commission of any HRB (yes/no), respectively. Poor sleep quality slightly elevated the risk for committing HRBs (PSQI Exp(B): 1.12 and ISI Exp(B): 1.07), and longer duration reduced the risk for HRBs to a greater extent (Exp(B): 0.78), even when controlling for a number of relevant demographic factors. Longer sleep duration also predicted a decreased risk for commission of any HRB behaviors (Exp(B): 0.71). These findings demonstrate that sleep quality and duration (the latter factor, in particular) could be targets for reducing excessive HRB in military populations. These findings could therefore lead to unit-wide or military-wide policy changes regarding sleep and HRB.
Leave against Medical Advice in Children: Rural Indian Perspective
Authors: Datta Debadyuti , Mondal Tanushree , Sarkar Mihir , Chel Soumita , Das Sankar Kumar , Nandy Arnab , M Ivan Divyoshanu , Mondal Rakesh
Published: October 2020

Objectives

To determine the burden and etiological factors of leave against medical advice (LAMA) in Indian children.

Methodology

In this prospective study, legal guardians of 528 patients who took the decision of LAMA were interviewed (using structured question answers based multi-option) and data were captured over a period of 16 months. The resultant database was analyzed using standard statistical methods.

Results

About 6.12% of childhood LAMA cases were dealt out of total pediatric admission including newborns. Neonatal preponderance noted in cases of LAMA from intensive care unit (ICU; 57.14%, p < 0.05). The overall male (n = 293) to female (n = 235) ratio in this study was 1.25:1. Number of LAMA patients was higher from rural area (83.33%), mostly admitted in ICU (93.65%, Pearson’s chi-squared test, p < 0.05). Higher proportion (29.47%) of patients with infection availed LAMA from neonatal age group but overall LAMA patients fall under category of respiratory disorders (22.35%). Interest of the domestics issues other than suffering child was considered primary during LAMA for those admitted in ward as compared with ICU patients [odds ratio (OR): 1.73, CI: 1.02–2.94, p < 0.05]. ICU patients were reportedly to be taken to private health care facility (OR: 1.93, CI: 1.06–3.49, p < 0.05). Duration of stay before taking LAMA from ward was <7 days (85.59%, OR: 0.19, CI: 0.11–0.35, p < 0.05). Upper-lower socio-economic class attributed financial constraint as the main reason for LAMA (Pearson’s chi-squared test, Chi-square value: 152.23, p < 0.05).

Conclusions

This study tried to elucidate the determinants of childhood LAMA in rural Indian setting.
Comprehensive screening of genomic and metagenomic data reveals a large diversity of tetracycline resistance genes
Authors: Berglund Fanny , Böhm Maria-Elisabeth , Martinsson Anton , Ebmeyer Stefan , Österlund Tobias , Johnning Anna , Larsson D. G. Joakim , Kristiansson Erik
Published: October 2020

Tetracyclines are broad-spectrum antibiotics used to prevent or treat a variety of bacterial infections. Resistance is often mediated through mobile resistance genes, which encode one of the three main mechanisms: active efflux, ribosomal target protection or enzymatic degradation. In the last few decades, a large number of new tetracycline-resistance genes have been discovered in clinical settings. These genes are hypothesized to originate from environmental and commensal bacteria, but the diversity of tetracycline-resistance determinants that have not yet been mobilized into pathogens is unknown. In this study, we aimed to characterize the potential tetracycline resistome by screening genomic and metagenomic data for novel resistance genes. By using probabilistic models, we predicted 1254 unique putative tetracycline resistance genes, representing 195 gene families (<70 % amino acid sequence identity), whereof 164 families had not been described previously. Out of 17 predicted genes selected for experimental verification, 7 induced a resistance phenotype in an

Escherichia coli

host. Several of the predicted genes were located on mobile genetic elements or in regions that indicated mobility, suggesting that they easily can be shared between bacteria. Furthermore, phylogenetic analysis indicated several events of horizontal gene transfer between bacterial phyla. Our results also suggested that acquired efflux pumps originate from proteobacterial species, while ribosomal protection genes have been mobilized from

Firmicutes

and

Actinobacteria

. This study significantly expands the knowledge of known and putatively novel tetracycline resistance genes, their mobility and evolutionary history. The study also provides insights into the unknown resistome and genes that may be encountered in clinical settings in the future.
Repurposing digitised clinical narratives to discover prognostic factors and predict survival in patients with advanced cancer
Authors: Lin Frank PY , Salih Osama SM , Scott Nina , Jameson Michael B , Epstein Richard J
Published: October 2020

Electronic medical records (EMR) represent a rich informatics resource that remains largely unexploited for improving healthcare outcomes. Here we report a systematic text mining analysis of EMR correspondence for 4791 cancer patients treated between 2001 and 2017. Meaningful groups of text descriptors correlating with poor survival outcomes were systematically identified, and applying machine learning analysis to clinical text accurately predicted cancer patient survival at selected timepoints up to 12 months. In a validation cohort of 726 patients, inclusion of EMR descriptors to machine learning models outperformed the predictivity of conventional clinical symptom scores by 4.9% (p = 0.001). These results prove that labour-intensive EMR data collection can be repurposed to add clinical value. Extension of this approach to a broader spectrum of digital health data should transform the real-time utility of such latent informatics resources, enabling healthcare systems to be more adaptive and responsive to patient circumstances.
Leveraging big data for classification of children who stutter from fluent peers
Authors: Rutherford Saige , Angstadt Mike , Sripada Chandra , Chang Soo-Eun
Published: October 2020

Introduction

Large datasets, consisting of hundreds or thousands of subjects, are becoming the new data standard within the neuroimaging community. While big data creates numerous benefits, such as detecting smaller effects, many of these big datasets have focused on non-clinical populations. The heterogeneity of clinical populations makes creating datasets of equal size and quality more challenging. There is a need for methods to connect these robust large datasets with the carefully curated clinical datasets collected over the past decades.

Methods

In this study, resting-state fMRI data from the Adolescent Brain Cognitive Development study (N=1509) and the Human Connectome Project (N=910) is used to discover generalizable brain features for use in an out-of-sample (N=121) multivariate predictive model to classify young (3-10yrs) children who stutter from fluent peers.

Results

Accuracy up to 72% classification is achieved using 10-fold cross validation. This study suggests that big data has the potential to yield generalizable biomarkers that are clinically meaningful. Specifically, this is the first study to demonstrate that big data-derived brain features can differentiate children who stutter from their fluent peers and provide novel information on brain networks relevant to stuttering pathophysiology.

Discussion

The results provide a significant expansion to previous understanding of the neural bases of stuttering. In addition to auditory, somatomotor, and subcortical networks, the big data-based models highlight the importance of considering large scale brain networks supporting error sensitivity, attention, cognitive control, and emotion regulation/self-inspection in the neural bases of stuttering.
FANCM regulates repair pathway choice at stalled replication forks
Authors: Panday Arvind , Willis Nicholas A. , Elango Rajula , Menghi Francesca , Duffey Erin E. , Liu Edison T. , Scully Ralph
Published: October 2020

Conservative repair of stalled replication forks is important for the maintenance of a stable genome. However, the mechanisms that regulate repair pathway “choice” at stalled mammalian forks remain poorly understood. The Fanconi anemia complementation group M gene,FANCM, encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here we use a chromosomally integrated reporter of stalled fork repair, in combination with defined mutations engineered within the endogenousFancmgene in primary mammalian cells, to study howFancmregulates stalled fork repair. We identify separation-of-functionFancmmutants, which reveal that distinct repair functions of FANCM are enacted by modular, molecularly separable scaffolding domains. These findings define FANCM as a key mediator of repair pathway choice at stalled replication forks and reveal its molecular mechanism. Notably, a mutation that inactivates the ATPase function of FANCM disables all FANCM-mediated repair functions and appears to “trap” FANCM at stalled forks. We find thatFancmnull cells do not survive genetic inactivation ofBrca1. This synthetic lethal interaction is recapitulated inFancmATPase-defective mutants. The ATPase function of FANCM may therefore represent a promising “druggable” target for therapy ofBRCA1mutant cancers.
Regulation of intracellular signaling and neuron function by Bardet-Biedl Syndrome proteins in patient-specific iPSC-derived neurons
Authors: Wang Liheng , Liu Yang , Stratigopoulos George , Panigrahi Sunil , Sui Lina , Leduc Charles A. , Glover Hannah J. , De Rosa Maria Caterina , Burnett Lisa C. , Williams Damian J. , Shang Linshan , Goland Robin , Tsang Stephen H. , Wardlaw Sharon , Egli Dieter , Zheng Deyou , Doege Claudia A. , Leibel Rudolph L.
Published: October 2020

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized by hyperphagic obesity. We developed a cellular model of BBS using induced pluripotent stem cell (iPSCs)-derived hypothalamic arcuate-like neurons. BBS mutationsBBS1M390RandBBS10C91fsX95did not affect neuron differentiation efficiency but caused morphological defects including impaired neurite outgrowth and longer primary cilia. Expression of intactBBS10normalized cilia length. Single-cell RNA sequencing (scRNA-seq) of BBS1M390Rhypothalamic neurons identified several down regulated pathways including insulin and cAMP signaling, and axon guidance. In agreement with scRNA-seq data, insulin-induced AKT phosphorylation at Thr308 was reduced inBBS1M390RandBBS10c91fsX95human fibroblasts and iPSC-derived neurons, as well as inBBS10knockdown iPSC-derived neurons. Overexpression of intactBBS10fully restored insulin receptor tyrosine phosphorylation inBBS10c91fsX95neurons. Mutations inBBS1andBBS10impaired leptin-mediated p-STAT3 activation in both human primary fibroblasts and iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling.POMCexpression inBBS1M390RandBBS10C91fsX95iPSC-derived hypothalamic neurons was downregulated, as was hypothalamicPomcin BBS1M390Rknockin (KI) mice. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBsome in CNS primary cilia mediate effects on energy homeostasis.
Global population structure and genotyping framework for genomic surveillance of the major dysentery pathogen,Shigella sonnei
Authors: Hawkey Jane , Paranagama Kalani , Baker Kate S. , Bengtsson Rebecca J. , Weill François-Xavier , Thomson Nicholas R. , Baker Stephen , Cerdeira Louise , Iqbal Zamin , Hunt Martin , Ingle Danielle J. , Dallman Timothy J. , Jenkins Claire , Williamson Deborah A. , Holt Kathryn E.
Published: October 2020

Shigella sonneiis the most common agent of shigellosis in high-income countries, and causes a significant disease burden in low- and middle-income countries. Antimicrobial resistance is increasingly common in all settings. Whole genome sequencing (WGS) is increasingly utilised forS. sonneioutbreak investigation and surveillance, but comparison of data between studies and labs is challenging. Here, we present a genomic framework and genotyping scheme forS. sonneito efficiently identify genotype and resistance determinants from WGS data. The scheme is implemented in the software package Mykrobe and tested on thousands of genomes. Applying this approach to analyse >4,000S. sonneiisolates sequenced in public health labs in three countries identified several common genotypes associated with increased rates of ciprofloxacin resistance and azithromycin resistance, confirming intercontinental spread of highly-resistantS. sonneiclones and demonstrating the genomic framework can facilitate monitoring of the emergence and spread of resistant clones at local and global scales.
CuBlock: A cross-platform normalization method for gene-expression microarrays
Authors: Junet Valentin , Farrés Judith , Mas José M. , Daura Xavier
Published: October 2020

Motivation

Cross-(multi)platform normalization of gene-expression microarray data remains an unresolved issue. Despite the existence of several algorithms, they are either constrained by the need to normalize all samples of all platforms together, compromising scalability and reuse, by adherence to the platforms of a specific provider, or simply by poor performance. In addition, many of the methods presented in the literature have not been specifically tested against multi-platform data and/or other methods applicable in this context. Thus, we set out to develop a normalization algorithm appropriate for gene-expression studies based on multiple, potentially large microarray sets collected along multiple platforms and at different times, applicable in systematic studies aimed at extracting knowledge from the wealth of microarray data available in public repositories; for example, for the extraction of Real-World Data to complement data from Randomized Controlled Trials. Our main focus or criterion for performance was on the capacity of the algorithm to properly separate samples from different biological groups.

Results

We present CuBlock, an algorithm addressing this objective, together with a strategy to validate cross-platform normalization methods. To validate the algorithm and benchmark it against existing methods, we used two distinct data sets, one specifically generated for testing and standardization purposes and one from an actual experimental study. Using these data sets, we benchmarked CuBlock against ComBat (Johnsonet al., 2007), YuGene (Lê Caoet al., 2014), DBNorm (Menget al., 2017), Shambhala (Borisovet al., 2019) and a simple log2transform as reference. We note that many other popular normalization methods are not applicable in this context. CuBlock was the only algorithm in this group that could always and clearly differentiate the underlying biological groups after mixing the data, from up to six different platforms in this study.

Availability

CuBlock can be downloaded fromhttps://www.mathworks.com/matlabcentral/fileexchange/77882-cublock

Contact

xouse@anaxomics.com,xavier.daura@uab.cat

Supplementary information

Supplementary data are available atbioRxivonline.
Amyloid ß Impacts Future Freezing of Gait in Parkinson’s Disease Via White Matter Hyperintensities
Authors: Dadar Mahsa , Miyasaki Janis , Duchesne Simon , Camicioli Richard
Published: October 2020

Background

Freezing of gait (FOG) is a common symptom in Parkinson’s Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage.

Objectives

To assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other.

Methods

We used baseline MRI and longitudinal gait data from the Parkinson’s Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG.

Results

SN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels.

Conclusions

Amyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.