bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the spatiotemporal variability of Alzheimer’s disease pathology
Authors: Vogel Jacob W. , Young Alexandra L. , Oxtoby Neil P. , Smith Ruben , Ossenkoppele Rik , Strandberg Olof T. , La Joie Renaud , Aksman Leon M. , J Grothe Michel , Iturria-Medina Yasser , Pontecorvo Michael J. , Devous Michael D. , Rabinovici Gil D. , Alexander Daniel C. , Hyoung Lyoo Chul , Evans Alan C. , Hansson Oskar ,   for the Alzheimer’s Disease Neuroimaging Initiative✶
Published: August 2020

Alzheimer’s disease (AD) is characterized by the progressive spread of tau pathology throughout the cerebral cortex. The pattern of spread is thought to be fairly consistent across individuals, though more recent work has demonstrated substantial variability in the AD population that is often associated with distinct clinical phenotypes. Still, a systematic, unbiased, wholebrain characterization of spatiotemporal variation in tau deposition in AD is lacking. We analyzed 1612 tau-PET scans and applied to this sample a disease progression modeling framework designed to identify spatiotemporal trajectories of pathological progression. We identified four distinct trajectories of tau progression, ranging in prevalence from 18–33%, with no one progession predominating. We replicated previously described limbic-predominant and medial temporal lobe-sparing variants, while also discovering posterior and lateral temporal subtypes resembling atypical clinical variants of AD. These “subtypes” were stable during longitudinal follow-up, and could be replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes, however, no “typical” variant predominated. Across all subtypes, younger age was related to worse cognition and more rapid tau accumulation. Additionally, network diffusion models implicated that pathology originates and spreads through distinct corticolimbic in the different subtypes. Together, our results suggest variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of “typical AD”, and a revisiting of tau pathological staging.
CG7379/ING1 suppress cancer cell invasion by maintaining cell-cell junction integrity
Authors: Rusu Alexandra D. , Cornhill Zoe E. , Coutino Brenda Canales , Uribe Marcos Castellanos , Lourdusamy Anbarasu , Markus Zsuzsa , May Sean T. , Rahman Ruman , Georgiou Marios
Published: August 2020

Approximately 90% of cancer related deaths can be attributed to a tumour’s ability to spread. We have identified CG7379, the fly orthologue of human ING1, as a potent invasion suppressor. ING1 is a type II tumour suppressor with well-established roles in the transcriptional regulation of genes that control cell proliferation, response to DNA damage, oncogene-induced senescence and apoptosis. Recent work suggests a possible role for ING1 in cancer cell invasion and metastasis, but the molecular mechanism underlying this observation is lacking. Our results show that reduced expression of CG7379 promotes invasion in vivo inDrosophila, reduces the junctional localisation of several adherens and septate junction components, and severely disrupts cell-cell junction architecture. Similarly, ING1 knockdown significantly enhances invasion in vitro and disrupts E-cadherin distribution at cell-cell junctions. A transcriptome analysis reveals that loss of ING1 affects the expression of several junctional and cytoskeletal modulators, confirming ING1 as an invasion suppressor and a key regulator of cell-cell junction integrity.
Phosphate binding induced force-reversal occurs via slow backward cycling of cross-bridges
Authors: Stehle R
Published: August 2020

The release of inorganic phosphate (Pi) from the cross-bridge is a pivotal step in the cross-bridge ATPase cycle leading to force generation. It is well known that Pirelease and the force-generating step are reversible, thus increase of [Pi] decreases isometric force by product inhibition and increases the rate constantkTRof mechanically-induced force redevelopment due to the reversible redistribution of cross-bridges among non-force-generating and force-generating states. The experiments on cardiac myofibrils from guinea pig presented here show that increasing [Pi] increaseskTRalmost reciprocally to force, i.e.,kTR≈ 1/force. To elucidate which cross-bridge models can explain the reciprocalkTR-force relation, simulations were performed for models varying in sequence and kinetics of 1) the Pirelease-rebinding equilibrium, 2) the force-generating step and its reversal, and 3) the transitions limiting forward and backward cycling of cross-bridges between non-force-generating and force-generating states. Models consisting of fast reversible force generation before/after rapid Pirelease-rebinding fail to describe thekTR–force relation observed in experiments. Models consistent with the experimentalkTR-force relation have in common that Pibinding and/or force-reversal are/is intrinsically slow, i.e., either Pibinding or force-reversal or both limit backward cycling of cross-bridges from force-generating to non-force-generating states.

STATEMENT OF SIGNIFICANCE

Previous mechanical studies on muscle fibers, myofibrils and myosin interacting with actin revealed that force production associated to phosphate release from myosin’s active site presents a reversible process in the cross-bridge cycle. The correlation of this reversible process to the process(es) limiting kinetics of backward cycling from force-generating to non-force-generating states remained unclear.

Experimental data of cardiac myofibrils and model simulations show that the combined effects of [Pi] on force and the rate constant of force redevelopment (kTR) are inconsistent with fast reversible force generation before/after rapid Pirelease-rebinding. The minimum requirement in sequential models for successfully describing the experimentally observed nearly reciprocal change of force andkTRis that either the Pibinding or the force-reversal step limit backward cycling.
Platelet-to-lymphocyte ratio (PLR), a novel biomarker to predict the severity of COVID-19 patients: a systematic review and meta-analysis
Authors: Simadibrata Daniel Martin , Pandhita Bashar Adi Wahyu , Ananta Muammar Emir , Tango Tamara
Published: August 2020

Background

Platelet-to-lymphocyte ratio (PLR), a novel inflammatory marker, has been suggested to be able to predict the severity of COVID-19 patients. This systematic review aims to evaluate the association between PLR levels on admission and the severity of COVID-19 patients.

Methods

A systematic literature search was done on 23 July 2020 to identify peer-reviewed studies across four different databases (Ovid MEDLINE, EMBASE, SCOPUS, and the Cochrane Library), preprints from two databases (MedRxiv and SSRN), and grey literature from two databases (WHO COVID-19 Global Research Database and Center for Disease Control and Prevention COVID-19 Research Article). Research articles comparing the PLR value on admission in adult patients with COVID-19 with varying degrees of severity were included in the analysis. The following keywords were used for the search: “COVID-19”, “PLR”, “severity”, and “mortality”. The inverse variance method was used to calculate the pooled effect standardized mean difference (SMD) along with its 95% confidence interval (CI).

Results

A total of seven studies were included in the meta-analysis, six of which were conducted in China. From a total of 998 participants included, 316 (31.7%) had severe diseases; and those in the severe group were generally older and had underlying diseases compared to the non-severe group. In comparison to non-severe patients, the meta-analysis showed that severe COVID-19 patients had higher PLR levels on admission (SMD 0.68; 95%CI 0.43-0.93; I2 =58%).

Conclusion

High PLR levels on admission were associated with severe COVID-19 cases. Therefore, on-admission PLR level is a novel, cost-effective, and readily available biomarker with a promising prognostic role for determining the severity of COVID-19 patients.
Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility
Authors: van Blokland Irene V. , Lanting Pauline , Ori Anil P.S. , Vonk Judith M. , Warmerdam Robert C.A. , Herkert Johanna C. , Boulogne Floranne , Claringbould Annique , Lopera-Maya Esteban A. , Bartels Meike , Hottenga Jouke-Jan , Ganna Andrea , Karjalainen Juha ,   Lifelines COVID-19 cohort study,   The COVID-19 Host Genetics Initiative, Hayward Caroline , Fawns-Ritchie Chloe , Campbell Archie , Porteous David , Cirulli Elizabeth T. , Barrett Kelly M. Schiabor , Riffle Stephen , Bolze Alexandre , White Simon , Tanudjaja Francisco , Wang Xueqing , Ramirez Jimmy M. , Lim Yan Wei , Lu James T. , Washington Nicole L. , de Geus Eco J.C. , Deelen Patrick , Boezen H. Marike , Franke Lude H.
Published: August 2020

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict potential COVID-19 cases using cross-sectional self-reported disease-related symptoms. Using a previously reported COVID-19 prediction model, we show that it is possible to conduct a GWAS on predicted COVID-19, and this GWAS benefits from the larger sample size to provide new insights into the genetic susceptibility of the disease. Furthermore, we find suggestive evidence that genetic variants for other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. Our findings demonstrate the added value of using self-reported symptom assessments to quickly monitor novel endemic viral outbreaks in a scenario of limited testing. Should there be another outbreak of a novel infectious disease, we recommend repeatedly collecting data of disease-related symptoms.
Homologous and heterologous antibodies to coronavirus 229E, NL63, OC43, HKU1, SARS, MERS and SARS-CoV-2 antigens in an age stratified cross-sectional serosurvey in a large tertiary hospital in The Netherlands
Authors: Westerhuis Brenda M. , de Bruin Erwin , Chandler Felicity D. , Ramakers Chris R. B. , Okba Nisreen M.A. , Li Wentao , Goossens Herman , de Jong Menno D. , Bosch Berend Jan , Haagmans Bart L. , Fraaij Pieter L. A. , Sikkema Reina S. , Koopmans Marion P.G.
Published: August 2020

Understanding the coronavirus (CoV) antibody landscape in relation to disease and susceptibility is critical for modelling of steps in the next phase during the current covid-19 pandemic. In March 2020, during the first month of the epidemic in The Netherlands, we performed cross sectional studies at two time points amongst patients of the Erasmus Medical Centre in Rotterdam, to assess the presence of antibodies against seasonal human coronaviruses (OC43, 229E, NL63, HKU1), emerging zoonotic coronaviruses (SARS, MERS) and SARS-CoV-2 in nine different age groups. We observed minimal SARS-CoV-2 reactivity early March (0.7% of sera), increasing to 3.0%, four weeks later, suggesting probably undetected cases during this early phase of the epidemic. Antibody responses were mostly coronavirus species specific at young age, but possible cross-reactivity between human seasonal CoVs was observed with increasing age.
Prevalence and outcome of Covid-19 infection in cancer patients: a national VA study
Authors: Fillmore Nathanael R. , La Jennifer , Szalat Raphael E. , Tuck David P. , Nguyen Vinh , Yildirim Cenk , Do Nhan V. , Brophy Mary T. , Munshi Nikhil C.
Published: August 2020

Background

Emerging data suggest variability in susceptibility and outcome to Covid-19 infection. Identifying the risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations.

Methods

We analyzed electronic health records of the US National Veterans Administration healthcare system and assessed the prevalence of Covid-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for Covid-19 and their confirmed positivity, with clinical characteristics, and outcome, and stratified by demographics, comorbidities, cancer treatment and cancer type.

Results

Of 22914 cancer patients tested for Covid-19, 1794 (7.8%) were positive. The prevalence of Covid-19 was similar across all ages. Higher prevalence was observed in African-American (AA) (15%) compared to white (5.5%; P<.001), in Hispanic vs non-Hispanic population and in patients with hematologic malignancy compared to those with solid tumors (10.9% vs 7.7%; P<.001). Conversely, prevalence was lower in current smoker patients, patients with other co-morbidities and having recently received cancer therapy (< 6 months). The Covid-19 attributable mortality was 10.9%. Highest mortality rates were observed in older patients, those with renal dysfunction, higher Charlson co-morbidity score and with certain cancer types. Recent (< 6 months) or past treatment did not influence mortality. Importantly, AA patients had 3.5-fold higher Covid-19 attributable hospitalization, however had similar mortality rate as white patients.

Conclusion

Pre-existence of cancer affects both susceptibility to Covid-19 infection and eventual outcome. The overall Covid-19 attributable mortality in cancer patients is affected by age, co-morbidity and specific cancer types, however, race or recent treatment including immunotherapy does not impact outcome.

Fundings

VA Office of Research and Development and National Institutes of Health.
Modeling Hospital Energy and Economic Costs for COVID-19 Infection Control Interventions
Authors: Squire Marietta M. , Munsamy Megashnee , Lin Gary , Telukdarie Arnesh , Igusa Takeru
Published: August 2020

The objective of this study was to assess the energy demand and economic cost of two hospital-based COVID-19 infection control interventions. The intervention control measures evaluated include use of negative pressure (NP) treatment rooms and xenon pulsed ultraviolet (XP-UV) infection control equipment. After projecting COVID-19 hospitalizations, a Hospital Energy Model and Infection De-escalation Models are applied to quantify increases in energy demand and reductions in secondary infections. The scope of the interventions consisted of implementing NP in 11, 22, and 44 rooms (at small, medium, and large hospitals) while the XP-UV equipment was used eight, nine, and ten hours a day, respectively. The annum kilowatt-hours (kWh) for NP (and costs were at $0.1015 per kWh) were 116,700 ($11,845), 332,530 ($33,752), 795,675 ($80,761) for small, medium, and large hospitals ($1,077, $1,534 $1,836 added annum energy cost per NP room). For XP-UV, the annum kilowatt-hours and costs were 438 ($45), 493 ($50), 548 ($56) for small, medium, and large hospitals. There are other initial costs associated with the purchase and installation of the equipment, with XP-UV having a higher initial cost. XP-UV had a greater reduction in secondary COVID-19 infections in large and medium hospitals. NP rooms had a greater reduction in secondary SARS-CoV-2 transmission in small hospitals. Early implementation of interventions can result in realized cost savings through reduced hospital-acquired infections.
Genomic surveillance revealed prevalence of unique SARS-CoV- 2 variants bearing mutation in the RdRp gene among Nevada patients
Authors: Hartley Paul D. , Tillett Richard L. , AuCoin David P. , Sevinsky Joel R. , Xu Yanji , Gorzalski Andrew , Pandori Mark , Buttery Erin , Hansen Holly , Picker Michael A. , Rossetto Cyprian C. , Verma Subhash C.
Published: August 2020

Patients with signs of COVID-19 were tested with CDC approved diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from nasopharyngeal/nasal swabs. In order to determine the variants of SARS-CoV-2 circulating in the state of Nevada, 200 patient specimens from positively identified cases were sequenced through our robust protocol for sequencing SARS-CoV-2 genomes from the nasopharyngeal or nasal swabs. This protocol enabled the identification of specific nucleotide variants including those coding for D614G and clades defining mutations. Additionally, these sequences were used for determining the phylogenetic relationships of SARS-CoV-2 genomes of public health importance occurring in the state of Nevada. Our study reports the occurrence of a novel variant in the nsp12 (RdRp-RNA dependent RNA Polymerase) protein at residue 323 (314aa of orf1b) to Phenylalanine (F) from Proline (P), present in the original isolate of SARS-CoV-2 (Wuhan-Hu-1). This 323F variant is found at a very high frequency (46% of the tested specimen) in Northern Nevada, possibly because the virus accumulated this mutation while circulating in the community and the shelter in place orders restricted the introduction and spread of other variants into this region. Structural modeling of the RdRp with P323F variant did not show any significant difference in protein conformation, but the phenotypic effect is unknown and an area of active investigation. In conclusion, our results highlight the introduction and spread of specific SARS-CoV-2 variants at very high frequency within a distinct geographic location that is important for clinical and public health perspectives in understanding the evolution and transmission of SARS-CoV-2.

IMPORTANCE

SARS-COV-2 genomes accumulate nucleotide mutations while passing in the human population and these mutations may confer phenotypic differences including altered immune response and anti-viral drug resistance. We developed a robust workflow to sequence SARS-CoV-2 directly from the nasal/nasopharyngeal swabs containing even a very low viral loads (>35 Ct value samples). Our protocol does not rely on amplicon based sequencing strategies nor the need of passing the virus into tissue culture thus reduces the possibility of an introduction of laboratory-adapted mutations. Sequences of SARS-CoV-2 from the patients of the state of Nevada during early months of the pandemic identified a rare mutation in the RdRp protein (P323F). This mutation occurred at a very high frequency in the variants of SARS-CoV-2 circulating Northern Nevada. Identification of such variants is important for clinical and public health perspectives in understanding transmission mediated evolution of SARS-CoV-2 variants and their implications on therapeutics and diagnostics.
Development and validation of 2D-LiDAR-based gait analysis instrument and algorithm
Authors: Yoon Seongjun , Jung Hee-Won , Jung Heeyoune , Kim Keewon , Koo Hong Suk , Roh Hyunchul , Oh Byung-Mo
Published: August 2020

Acquiring gait parameters from usual walking is important to predict clinical outcomes, including life expectancy, risk of fall, and neurocognitive performance, in older people. For comprehensive gait analysis, instruments such as marker-based motion analysis systems and walkways with pressure sensor arrays are necessary. Traditional instruments are bulky, complex, expensive, and intrinsically intrusive. Requirements of dedicated spaces for installation and specialized staff make it difficult to utilize traditional gait analysis instruments in most outpatient clinics. We present a novel gait analysis tool that is small, highly accurate, easy-to-use, and non-intrusive and is based on two-dimensional light detection and ranging technology. Using an object-tracking algorithm, we conducted a validation study of spatiotemporal tracking of ankle locations of subjects by comparing our tool with a gold standard modality. Our tool showed successful acquisition of gait parameters from usual walking motions and trackability with multiple targets in noisy conditions, including typical clinical environments.
Dynamics of the Gut Microbiota in MEBO and PATM conditions: Protocol of a fully remote clinical study
Authors: Gabashvili Irene S.
Published: August 2020

The proposed study will identify microbial communities associated with flare ups and remissions of MEBO (systemic malodor of metabolic origin) or PATM (“People allergic to me”) conditions.

Background

Human odor-prints, mostly owing to the microbiome, have proven their value as biomarkers of health and environmental exposures.

In recent years, microbial networks responsible for localized malodors (e.g., halitosis [1,2], groin area, foot and axillary odor [3,4]) have been mapped by using next generation sequencing approaches.

Intestinal microbes responsible for psychologically debilitating systemic malodor (whole-body and extraoral halitosis), however, remain to be identified. Even a relatively straightforward disorder of choline metabolism trimethylaminuria (TMAU) is thought to exhibit complex host-gene microbiome interactions [5] and has not been sufficiently studied.

Mapping gut microbiome is needed to understand human metabolic disfunction, make proper dietary recommendations and develop targeted treatments such as microbial therapies [6–8]. Our preliminary analysis of culture-, PCR- and 16S-RNA-based data found several Operational Taxonomic Units (OTUs) potentially linked to systemic malodor. Proposed controlled pilot study will provide a more comprehensive evaluation and, combined with our prior data [9–12], will help to develop new therapies and treatments.
Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125
Authors: Wang Yu-Hung , Lin Chien-Chin , Hsu Chia-Lang , Hung Sheng-Yu , Yao Chi-Yuan , Lee Sze-Hwei , Tsai Cheng-Hong , Hou Hsin-An , Chou Wen-Chien , Tien Hwei-Fang
Published: August 2020

Expression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study was aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with FLT3-ITD, RUNX1, and DNMT3A mutations, and M1 subtype by the French-American-British classification, but inversely correlated with t(8;21) and t(15;17). Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.
Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison
Authors: Galani Ioanna-Evdokia , Rovina Nikoletta , Lampropoulou Vicky , Triantafyllia Vasiliki , Manioudaki Maria , Pavlos Eleftherios , Koukaki Evangelia , Fragkou Paraskevi C. , Panou Vasiliki , Rapti Vasiliki , Koltsida Ourania , Mentis Andreas , Koulouris Nikolaos , Tsiodras Sotirios , Koutsoukou Antonia , Andreakos Evangelos
Published: August 2020

A central paradigm of immunity is that interferon (IFN) mediated antiviral responses precede the pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for COVID-19 this does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 COVID-19 patients hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production is both diminished and delayed, induced only in a fraction of patients as they become critically ill. On the contrary, pro-inflammatory cytokines such as TNF, IL-6 and IL-8 are produced before IFNs, in all patients, and persist for a prolonged time. By comparison, in 16 flu patients hospitalized for pneumonia with similar clinicopathological characteristics to COVID-19 and 24 milder non-hospitalized flu patients IFN-λ and type I IFN are robustly induced, earlier, at higher levels and independently of disease severity, while pro-inflammatory cytokines are only acutely and transiently produced. Notably, higher IFN-λ levels in COVID-19 patients correlate with lower viral load in bronchial aspirates and faster viral clearance, and a higher IFN-λ:type I IFN ratio with improved outcome of critically ill patients. Moreover, altered cytokine patterns in COVID-19 patients correlate with longer hospitalization time and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19 contributing to persistent viral presence, hyperinflammation and respiratory failure.
Differential shared genetic influences on anxiety with problematic alcohol use compared to alcohol consumption
Authors: Colbert Sarah M. C. , Funkhouser Scott A. , Johnson Emma C. , Hoeffer Charles , Ehringer Marissa A. , Evans Luke M.
Published: August 2020

Anxiety disorders and alcohol use disorders are common psychiatric illnesses. Comorbidity of the two disorders can have a tremendous effect on treatment of one or both disorders, as well as an individual’s social, economic, and physical well-being. We estimated genome-wide genetic correlations between anxiety and alcohol use traits using linkage disequilibrium score regression (LDSC) and found strong and positive correlations of anxiety with problematic alcohol use (PAU), but not with most alcohol consumption (AC) measures. We observed strong, positive between-sex genetic correlations for all traits, but found suggestive evidence that the genetic correlation between alcohol use and anxiety might differ between males and females. Estimates of local genetic covariance demonstrated divergent genetic covariance profiles of PAU and AC with anxiety phenotypes and localized 12 specific genomic regions that likely contribute to both anxiety and alcohol use. Finally, partitioning the genetic covariance among functional annotations also identified the amygdala, caudate basal ganglia and frontal cortex as contributing significantly to positive genetic covariance between anxiety and PAU phenotypes. This study serves as a framework for an approach to be used in future analyses of the genetics of comorbid disorders.
The unintended consequences of inconsistent pandemic control policies
Authors: Althouse Benjamin M. , Wallace Brendan , Case Brendan , Scarpino Samuel V. , Berdahl Andrew M. , White Easton R. , Hébert-Dufresne Laurent
Published: August 2020

Controlling the spread of COVID-19 – even after a licensed vaccine is available – requires the effective use of non-pharmaceutical interventions, e.g., physical distancing, limits on group sizes, mask wearing, etc.. To date, such interventions have neither been uniformly nor systematically implemented in most countries. For example, even when under strict stay-at-home orders, numerous jurisdictions granted exceptions and/or were in close proximity to locations with entirely different regulations in place. Here, we investigate the impact of such geographic inconsistencies in epidemic control policies by coupling search and mobility data to a simple mathematical model of SARS-COV2 transmission. Our results show that while stay-at-home orders decrease contacts in most areas of the United States of America (US), some specific activities and venues often see an increase in attendance. Indeed, over the month of March 2020, between 10 and 30% of churches in the US saw increases in attendance; even as the total number of visits to churches declined nationally. This heterogeneity, where certain venues see substantial increases in attendance while others close, suggests that closure can cause individuals to find an open venue, even if that requires longer-distance travel. And, indeed, the average distance travelled to churches in the US rose by 13% over the same period. Strikingly, our mathematical model reveals that, across a broad range of model parameters, partial measures can often be worse than no measures at all. In the most severe cases, individuals not complying with policies by traveling to neighboring jurisdictions can create epidemics when the outbreak would otherwise have been controlled. Taken together, our data analysis and modelling results highlight the potential unintended consequences of inconsistent epidemic control policies and stress the importance of balancing the societal needs of a population with the risk of an outbreak growing into a large epidemic.
Formation of an Aminovinyl-Cysteine Residue in Thioviridamide Non-Lanthipeptides Occurs through a Path Independent of Known Lanthionine Synthetase Activity inStreptomyces sp. NRRL S-87
Authors: Qiu Yanping , Liu Jingyu , Li Yuqing , Xue Yanqing , Wang Huan , Liu Wen
Published: August 2020

2-Aminovinyl-cysteine (AviCys) is an unusual thioether amino acid shared by a variety of ribosomally synthesized and posttranslationally modified peptides (RiPPs), as part of a macrocyclic ring system that contains theC-terminal 4 or 6 residues of a precursor peptide. This amino acid is nonproteinogenic and arises from processing theC-terminal Cys residue and an internal Ser/Thr residue to form an unsaturated thioether linkage. Enzyme activities for forming lanthionine (Lan), a distinct saturated thioether residue characteristic of lanthipeptide-related RiPPs, has long been speculated to be necessary for AviCys formation. Based on investigations into the biosynthesis of thioviridamide non-lanthipeptdes inStreptomyces sp. NRRL S-87, we here report an alternative path for AviCys formation that is independent of known Lan synthetase activity. This path relies on four dedicated enzymes for posttranslational modifications of the precursor peptide, in which TvaES-87, a phosphotransferase homolog, plays a critical role. It works with LanD-like flavoprotein TvaFS-87to form a minimum AviCys synthetase complex that follows the combined activity of TvaCDS-87for Thr dehydration and catalyzes Cys oxidative decarboxylation and subsequent Michael addition of the resulting enethiol nucleophile onto the newly formed dehydrobutyrine residue for cyclization. With TvaES-87, TvaFS-87activity for Cys processing can be coordinated with TvaCDS-87activity for minimizing competitive or unexpected spontaneous reactions and forming AviCys effectively.
Do substrate roughness and gap distance impact gap-bridging strategies in arboreal chameleons
Authors: Luger Allison M. , Vincent Vermeylen , Anthony Herrel , Dominique Adriaens
Published: August 2020

Chameleons are well-equipped for an arboreal lifestyle, having ‘zygodactylous’ hands and feet as well as a fully prehensile tail. However, to what degree tail use is preferred over autopod prehension has been largely neglected. Using an indoor experimental set-up, where chameleons had to cross gaps of varying distances, we tested the effect of substrate diameter and roughness on tail use inChamaeleo calyptratus. Our results show that when crossing greater distances,C. calyptratusis more likely to use its tail for additional stability. The animals were able to cross greater distances (up to 1 75 times the shoulder-hip length) on perches with a rougher surface. We saw that depending on the distance of the gap, chameleons would change how they use their prehensile tails when crossing. With shorter gaps the tails either do not touch, or only touch the perch without coiling around it. With larger distances the tails are fully coiled around the perch, and with the largest distances additionally they reposition the hind legs, shifting them towards the end of the perch. Males were able to cross relatively greater distances than females, likely due to their larger size and strength.
MotiMul: A significant discriminative sequence motif discovery algorithm with multiple testing correction
Authors: Mori Koichi , Ozaki Haruka , Fukunaga Tsukasa
Published: August 2020

Sequence motifs play essential roles in intermolecular interactions such as DNA-protein interactions. The discovery of novel sequence motifs is therefore crucial for revealing gene functions. Various bioinformatics tools have been developed for finding sequence motifs, but until now there has been no software based on statistical hypothesis testing with statistically sound multiple testing correction. Existing software therefore could not control for the type-1 error rates. This is because, in the sequence motif discovery problem, conventional multiple testing correction methods produce very low statistical power due to overly-strict correction. We developed MotiMul, which comprehensively finds significant sequence motifs using statistically sound multiple testing correction. Our key idea is the application of Tarone’s correction, which improves the statistical power of the hypothesis test by ignoring hypotheses that never become statistically significant. For the efficient enumeration of the significant sequence motifs, we integrated a variant of the PrefixSpan algorithm with Tarone’s correction. Simulation and empirical dataset analysis showed that MotiMul is a powerful method for finding biologically meaningful sequence motifs. The source code of MotiMul is freely available athttps://github.com/ko-ichimo-ri/MotiMul.
Identifying Taxonomic Units in Metagenomic DNA Streams
Authors: Zheng Vicky , Sariyuce Ahmet Erdem , Zola Jaroslaw
Published: August 2020

With the emergence of portable DNA sequencers, such as Oxford Nanopore Technology MinION, metagenomic DNA sequencing can be performed in real-time and directly in the field. However, because metagenomic DNA analysis is computationally and memory intensive, and the current methods are designed for batch processing, the current metagenomic tools are not well suited for mobile devices.

In this paper, we propose a new memory-efficient method to identify Operational Taxonomic Units (OTUs) in metagenomic DNA streams. Our method is based on finding connected components in overlap graphs constructed over a real-time stream of long DNA reads as produced by MinION platform. We propose an efficient algorithm to maintain connected components when an overlap graph is streamed, and show how redundant information can be removed from the stream by transitive closures. Through experiments on simulated and real-world metagenomic data, we demonstrate that the resulting solution is able to recover OTUs with high precision while remaining suitable for mobile computing devices.
Route following by one-eyed ants suggests a revised model of normal route following
Authors: Woodgate Joseph L. , Perl Craig , Collett Thomas S.
Published: August 2020

The prevailing account of visually controlled routes is that an ant learns views as it follows a route, while guided by other path-setting mechanisms. Once a set of route views is memorised, the insect follows the route by turning and moving forwards when the view on the retina matches a stored view. We have engineered a situation in which this account cannot suffice in order to discover whether there may be additional components to the performance of routes. One-eyed wood ants were trained to navigate a short route in the laboratory guided by a single black, vertical bar placed in the blinded visual field. Ants thus had to turn away from the route to see the bar. They often turned to look at or beyond the bar and then turned to face in the direction of the goal. Tests in which the bar was shifted to be more peripheral or more frontal than in training produced a corresponding change in the ants’ paths, demonstrating that they were guided by the bar, presumably obtaining information during scanning turns towards the bar. Examination of the endpoints of turns away from the bar suggest that ants use the bar for guidance by learning how large a turn-back is needed to face the goal. We suggest that the ants’ zigzag paths are an integral part of visually guided route following. In addition, on some runs in which ants did not take a direct path to the goal, they still turned to face and sometimes approach the goal for a short stretch. This off-route goal facing indicates that they store a vector from start to goal and use path integration to track their position relative to the endpoint of the vector.
Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice
Authors: Lee Chang-Lung , Brock Kennedy Davis , Hasapis Stephanie , Zhang Dadong , Sibley Alexander B. , Qin Xiaodi , Gresham Jeremy , Caraballo Isibel , Luo Lixia , Daniel Andrea R. , Hilton Matthew J. , Owzar Kouros , Kirsch David G.
Published: August 2020

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-lymphoblastic leukemia/lymphoma. Here, we aimed to determine key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/-and KrasLA1mice were not observed to harbor significantly higher numbers of non-synonymous somatic mutations compared to thymic lymphomas from unirradiated p53-/-mice. However, we observed distinct patterns of recurrent mutations in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Using reporter mice for activation of the Notch1 signaling we observed that TBI enriched Notch1hiCD44+thymocytes, which are capable of self-renewalin vivo. Mechanistically, genetic inhibition of Notch1 signaling in thymocytes prevented the formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, our results demonstrate a critical role of activated Notch1 signaling in driving multi-step carcinogenesis of thymic lymphoma following total-body irradiation in p53 WT mice.
In vivo metabolite tracing of T cells
Authors: Sheldon Ryan D. , Ma Eric H. , DeCamp Lisa M. , Williams Kelsey S. , Jones Russell G.
Published: August 2020

T cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass spectrometry (MS)-based metabolomic profiling to assess T cell metabolismin vivo. In this protocol, pathogen-infected mice are infused via the tail vein with an isotopically labeled metabolite, followed by rapid magnetic bead isolation to purify T cell populations and then stable isotope labeling (SIL) analysis conducted by MS. This procedure enables researchers to evaluate metabolic substrate utilization by specific T cell subpopulations in the context of physiological immune responses in vivo.
A long read optimizedde novotranscriptome pipeline reveals novel ocular developmentally regulated gene isoforms and disease targets
Authors: Swamy Vinay S. , Fufa Temesgen D. , Hufnagel Robert B. , McGaughey David M.
Published: August 2020

De novotranscriptome construction from short-read RNA-seq is a common method for reconstructing mRNA transcripts within a given sample. However, the precision of this process is unclear as it is difficult to obtain a ground-truth measure of transcript expression. With advances in third generation sequencing, full length transcripts of whole transcriptomes can be accurately sequenced to generate a ground-truth transcriptome. We generated long-read PacBio and short-read Illumina RNA-seq data from a human induced pluripotent stem cell- derived retinal pigmented epithelium (iPSC-RPE) cell line. We use long-read data to identify simple metrics for assessingde novotranscriptome construction and optimize a short-read basedde novotranscriptome construction pipeline. We apply this this pipeline to construct transcriptomes for 340 short-read RNA-seq samples originating from healthy adult and fetal human retina, cornea, and RPE. We identify hundreds of novel gene isoforms and examine their significance in the context of ocular development and disease.
Detection of Discordant Peptide Quantities in Shotgun Proteomics Data by Peptide Correlation Analysis (PeCorA)
Authors: Meyer Jesse G.
Published: August 2020

Shotgun proteomics techniques infer the presence and quantity of proteins using peptide proxies, which are produced by cleavage of all isolated protein by a protease. Most protein quantitation strategies assume that multiple peptides derived from a protein will behave quantitatively similar across treatment groups, but this assumption may be false for biological or technical reasons. Here, I describe a strategy called peptide correlation analysis (PeCorA) that detects quantitative disagreements between peptides mapped to the same protein. Simple linear models are used to assess whether the slope of a peptide’s change across treatment groups differs from the slope of all other peptides assigned to the same protein. Reanalysis of proteomic data from primary mouse microglia with PeCorA revealed that about 15% of proteins contain one discordant peptide. Inspection of the discordant peptides shows utility of PeCorA for direct and indirect detection of regulated PTMs, and also for discovery of poorly quantified peptides that should be excluded. PeCorA can be applied to an arbitrary list of quantified peptides, and is freely available as a script written in R.
Computationally Guided Design of Novel Selective Serotonin Reuptake Inhibitors
Authors: Achyutuni Kavya G. , Adhikari Sambid , Huang Peishan , Siegel Justin B.
Published: August 2020

Current selective serotonin reuptake inhibitor (SSRI) drugs such as paroxetine, fluoxetine and escitalopram are prescribed for mental health conditions such as anxiety and depression. However, there are still several unpleasant side effects which fuels the need for new designs. In this work, computational studies were conducted to design two novel drug candidates with improved docking scores than paroxetine, an existing SSRI drug. Homology analysis was carried out to determine the suitability of an organism for preclinical trials and revealed laboratory mouse (Mus musculus) to be a good candidate.
Auxetic Two-Dimensional Nanostructures from DNA
Authors: Li Ruixin , Chen Haorong , Choi Jong Hyun
Published: August 2020

Architectured materials exhibit negative Poisson’s ratios and enhanced mechanical properties compared with regular materials. Their auxetic behaviors should emerge from periodic cellular structures regardless of the materials used. The majority of such metamaterials are constructed by top-down approaches and macroscopic with unit cells of microns or larger. On the other extreme, there are molecular-scale auxetics including naturally-occurring crystals which are not designable. There is a gap from few nanometers to microns, which may be filled by bottom-up biomolecular self-assembly. Here we demonstrate two-dimensional auxetic nanostructures using DNA origami. Structural reconfiguration experiments are performed by strand displacement and complemented by mechanical deformation studies using coarse-grained molecular dynamics (MD) simulations. We find that the auxetic properties of DNA nanostructures are mostly defined by geometrical designs, yet materials’ chemistry also plays an important role. From elasticity theory, we introduce a set of design principles for auxetic DNA metamaterials, which should find diverse applications.
geneRFinder: gene finding in distinct metagenomic data complexities
Authors: Silva Raíssa , Padovani Kleber , Góes Fabiana , Alves Ronnie
Published: August 2020

Motivation

Microbes perform a fundamental economic, social and environmental role in our society. Metagenomics makes it possible to investigate microbes in their natural environments (the complex communities) and their interactions. The way they act is usually estimated by looking at the functions they play in those environments and their responsibility is measured by their genes. The advances of next-generation sequencing technology have facilitated metagenomics research however it also create a heavy computational burden. Large and complex biological datasets are available as never before. There are many gene predictors available which can aid gene annotation process though they lack of handling appropriately metagenomic data complexities. There is no standard metagenomic benchmark data for gene prediction. Thus, gene predictors may inflate their results by obfuscating low false discovery rates.

Results

We introduce geneRFinder, a ML-based gene predictor able to outperform state-of-the-art gene prediction tools across this benchmark by using only one pre-trained Random Forest model. Average prediction rates of geneRFinder differed in percentage terms by 54% and 64%, respectively, against Prodigal and FragGeneScan while handling high complexity metagenomes. The specificity rate of geneRFinder had the largest distance against FragGeneScan, 79 percentage points, and 66 more than Prodigal. According to McNemar’s test, all percentual differences between predictors performances are statistically significant for all datasets with a 99% confidence interval.

Conclusions

We provide geneRFinder, a approach for gene prediction in distinct metagenomic complexities, available at github.com/railorena/geneRFinder, and also we provide a novel, comprehensive benchmark data for gene prediction — which is based on The Critical Assessment of Metagenome Interpretation (CAMI) challenge, and contains labeled data from gene regions – avaliable at sourceforge.net/p/generfinder-benchmark.
Hallucination of moving objects revealed by a dynamic noise background
Authors: Nakayama Ryohei , Holcombe Alex O.
Published: August 2020

We show that on a dynamic noise background, the perceived disappearance location of a moving object is shifted in the direction of motion. This “twinkle goes” illusion has little dependence on the luminance- or chromaticity-based confusability of the object with the background, or on the amount of background motion energy in the same direction as the object motion. This suggests that the illusion is enabled by the dynamic noise masking the offset transients that otherwise accompany an object’s disappearance. While these results are consistent with an anticipatory process that pre-activates positions ahead of the object’s current position, additional findings suggest an alternative account: a continuation of attentional tracking after the object disappears. First, the shift was greatly reduced when attention was divided between two moving objects. Second, the illusion was associated with a prolonging of the perceived duration of the object, by an amount that matched the extent of extrapolation inferred from the effect of speed on the size of the illusion (~50 ms). While the anticipatory extrapolation theory does not predict this, the continuation of attentional tracking theory does. Specifically, we propose that in the absence of offset transients, attentional tracking keeps moving for several tens of milliseconds after the target disappearance, and this causes one to hallucinate a moving object at the position of attention.