bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical characteristics of Covid-19 patients with re-positive test results: an observational study
Authors: Su Ying , Zhu Ling-Shuang , Gao Yong , Li Yuncheng , Xiong Zhanlu , Hu Bo , Yuan Jiao , Zhang Zhao , Wu Xiaoxiong , Feng Chunchen , Cheng Fanjun , Jin Yang , Zhang Yu , Lu Youming , Wang Hongbo , Zhu Ling-Qiang
Published: June 2020

Background

With coronavirus disease 2019 (Covid-19) ravaging the global, concern has been aroused whether discharged Covid-19 patients with reappeared positive nucleic acid test results are infected again.

Objective

To analyze the clinical characteristics of discharged Covid-19 patients with reappeared positive nucleic acid test results and to track clinical outcomes of them.

Methods

We extracted clinical data on 938 Covid-19 patients from Wuhan Union Hospital (West Branch), and we obtained information about residual symptoms and nucleic acid tests after discharge through follow-up study. We evaluated the relationship of clinical characteristics and reappeared positive results. Each patient had at least 44 days of follow-up.

Results

Of 938 discharged patients, a total of 58 (6.2%) had reappeared positive nucleic acid test results and 880 remain negative. Among patients over the age of 50, the factors we found to be associated with re-positive results were coronary artery disease (14.1%, vs. 5.5% among those without coronary artery disease; odds ratio, 2.81; 95% confidence interval [CI], 1.28 to 6.15), and hypertension (9.5%, vs. 4.9% among those without hypertension; odds ratio, 2.05; 95% CI, 1.10 to 3.82). As of May 11, 2020, 54 (93.1%) re-positive patients turned negative again while two patients remained positive, and two patients was lost to the second follow-up.

Conclusion

Coexisting diseases including coronary artery disease and hypertension were substantial risk factors for re-positive outcomes among patients over 50. And most re-positive patients tended to return negative eventually.
Generation of a DAT-Flp mouse line for intersectional genetic targeting of dopamine neuron subpopulations
Authors: Kramer Daniel J. , Kosillo Polina , Friedmann Drew , Stafford David , Luo Liqun , Lee Angus Yiu-Fai , Hockemeyer Dirk , Ngai John , Bateup Helen S.
Published: June 2020

Dopamine neurons project to diverse regions throughout the brain to modulate various brain processes and behaviors. It is increasingly appreciated that dopamine neurons are heterogeneous in their gene expression, circuitry, physiology, and function. Current approaches to target dopamine neurons are largely based on single gene drivers, which either label all dopamine neurons, or mark a sub-set but concurrently label non-dopaminergic neurons. Here we establish a novel mouse line in which Flp recombinase is knocked-in to the endogenousSlc6a3(dopamine active transporter, DAT) locus. DAT-Flp mice can be used with various Cre-expressing mouse lines to efficiently and selectively label dopaminergic subpopulations using Cre/Flp-dependent intersectional strategies. We demonstrate the utility of this approach by crossing DAT-Flp mice with NEX-Cre mice, to specifically labelNeurod6-expressing dopamine neurons that project to the nucleus accumbens medial shell. DAT-Flp mice represent a novel tool, which will help parse the diverse functions mediated by dopaminergic circuits.
Differential occupational risks to healthcare workers from SARS-CoV-2: A prospective observational study
Authors: Eyre David W , Lumley Sheila F , O’Donnell Denise , Campbell Mark , Sims Elizabeth , Lawson Elaine , Warren Fiona , James Tim , Cox Stuart , Howarth Alison , Doherty George , Hatch Stephanie B , Kavanagh James , Chau Kevin K , Fowler Philip W , Swann Jeremy , Volk Denis , Yang-Turner Fan , Stoesser Nicole E , Matthews Philippa C , Dudareva Maria , Davies Timothy , Shaw Robert H , Peto Leon , Downs Louise O , Vogt Alexander , Amini Ali , Young Bernadette C , Drennan Philip , Mentzer Alexander J , Skelly Donal , Karpe Fredrik , Neville Matt J , Andersson Monique , Brent Andrew J , Jones Nicola , Ferreira Lucas Martins , Christott Thomas , Marsden Brian D , Hoosdally Sarah , Cornall Richard , Crook Derrick W , Stuart David , Screaton Gavin ,   Oxford University Hospitals Staff Testing Group, Peto Timothy EA , Holthof Bruno , O’Donnell Anne-Marie , Ebner Daniel , Conlon Christopher P , Jeffery Katie , Walker Timothy M
Published: June 2020

Background

Personal protective equipment (PPE) and social distancing are designed to mitigate risk of occupational SARS-CoV-2 infection in hospitals. Why healthcare workers nevertheless remain at increased risk is uncertain.

Methods

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using nasopharyngeal PCR testing and immunoassays for IgG antibodies. A positive result by either modality determined a composite outcome. Risk-factors for Covid-19 were investigated using multivariable logistic regression.

Results

1083/9809(11.0%) staff had evidence of Covid-19 at some time and provided data on potential risk-factors. Staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.63 [95%CI 3.30-6.50]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (21.2% vs. 8.2% elsewhere) (aOR 2.49 [2.00-3.12]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.50 [1.05-2.15]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit (ICU) staff were relatively protected (0.46 [0.29-0.72]). Positive results were more likely in Black (1.61 [1.20-2.16]) and Asian (1.58 [1.34-1.86]) staff, independent of role or working location, and in porters and cleaners (1.93 [1.25-2.97]). Contact tracing around asymptomatic staff did not lead to enhanced case identification. 24% of staff/patients remained PCR-positive at ≥6 weeks post-diagnosis.

Conclusions

Increased Covid-19 risk was seen in acute medicine, among Black and Asian staff, and porters and cleaners. A bundle of PPE-related interventions protected staff in ICU.
Gamma band alterations and REM-like traits underpin the acute effect of the atypical psychedelic ibogaine
Authors: González Joaquín , Cavelli Matias , Castro-Zaballa Santiago , Mondino Alejandra , Tort Adriano BL , Rubido Nicolás , Carrera Ignacio , Torterolo Pablo
Published: June 2020

Ibogaine is a psychedelic alkaloid that has attracted scientific interest because of its important antiaddictive properties evidenced in observational studies in humans, and in models for substance-use-disorders in rodents. Its subjective effect has been described as intense vivid dream-like experiences occurring while awake; hence, ibogaine is often referred to as an oneirogenic psychedelic. While this unique dream-like profile has been hypothesized to aid the antiaddictive effects in the past, the electrophysiological signatures of the ibogaine psychedelic state remain unknown. In our previous work, we showed in rats that ibogaine administration promotes a waking state with abnormal motor behavior, accompanied by a decrease in NREM and REM sleep. Here, we performed an in-depth analysis of the intracranial electroencephalogram during “ibogaine wakefulness”. Ibogaine induced gamma oscillations with larger power than control levels but less coherent and less complex; i.e., this state shows clear REM sleep traits within the gamma frequency band. Thus, our results provide novel biological evidence for the association between the psychedelic state and REM sleep, and an empirical basis for the oneirogenic conjecture of ibogaine.
Effects of estradiol on biological age measured using the glycan age index
Authors: Jurić Julija , Kohrt Wendy M. , Kifer Domagoj , Pezer Marija , Nigrovic Peter A. , Lauc Gordan
Published: June 2020

Glycan age is a recently developed biomarker based on glycans attached to immunoglobulin G (IgG). In large population cohorts glycan age associates well with lifestyle and disease-risk biomarkers, while some studies suggested that change in glycans precede development of several age-associated diseases. In this study we evaluated effects of estrogen on the glycan age. Gonadal hormones were suppressed in 36 healthy young women by gonadotropin releasing hormone agonist therapy for 6 months. In 15 of them estradiol was supplemented, while 21 received placebo resulting in very low estrogen levels during intervention. IgG was isolated from plasma samples before intervention, after 6 months of intervention and after subsequent 4-month recovery. In the placebo group the removal of gonadal hormones resulted in median increase of glycan age for 9.1 years (IQR 6.8 – 11.5 years, p = 3.73×10−8), which was completely prevented by transdermal estradiol supplementation. After the recovery period glycan age returned to baseline values also in the placebo group. These results suggest that IgG glycans and consequently also the glycan age are under strong influence of gonadal hormones and that hormone replacement therapy can prevent the increase of glycan age that occurs in the perimenopausal period.
Training recurrent spiking neural networks in strong coupling regime
Authors: Kim Christopher M. , Chow Carson C.
Published: June 2020

Recurrent neural networks trained to perform complex tasks can provide insights into the dynamic mechanism that underlies computations performed by cortical circuits. However, due to a large number of unconstrained synaptic connections, the recurrent connectivity that emerges from network training may not be biologically plausible. Therefore, it remains unknown if and how biological neural circuits implement dynamic mechanisms proposed by the models. To narrow this gap, we developed a training scheme that, in addition to achieving learning goals, respects the structural and dynamic properties of a standard cortical circuit model, i.e., strongly coupled excitatory-inhibitory spiking neural networks. By preserving the strong mean excitatory and inhibitory coupling of initial networks, we found that most of trained synapses obeyed Dale’s law without additional constraints, exhibited large trial-to-trial spiking variability, and operated in inhibition-stabilized regime. We derived analytical estimates on how training and network parameters constrained the changes in mean synaptic strength during training. Our results demonstrate that training recurrent neural networks subject to strong coupling constraints can result in connectivity structure and dynamic regime relevant to cortical circuits.
Large-scale association analyses identify host factors influencing human gut microbiome composition
Authors: Kurilshikov Alexander , Medina-Gomez Carolina , Bacigalupe Rodrigo , Radjabzadeh Djawad , Wang Jun , Demirkan Ayse , Roy Caroline I. Le , Raygoza Garay Juan Antonio , Finnicum Casey T. , Liu Xingrong , Zhernakova Daria V. , Bonder Marc Jan , Hansen Tue H. , Frost Fabian , Rühlemann Malte C. , Turpin Williams , Moon Jee-Young , Kim Han-Na , Lüll Kreete , Barkan Elad , Shah Shiraz A. , Fornage Myriam , Szopinska-Tokov Joanna , Wallen Zachary D. , Borisevich Dmitrii , Agreus Lars , Andreasson Anna , Bang Corinna , Bedrani Larbi , Bell Jordana T. , Bisgaard Hans , Boehnke Michael , Boomsma Dorret I. , Burk Robert D. , Claringbould Annique , Croitoru Kenneth , Davies Gareth E. , van Duijn Cornelia M. , Duijts Liesbeth , Falony Gwen , Fu Jingyuan , van der Graaf Adriaan , Hansen Torben , Homuth Georg , Hughes David A. , Ijzerman Richard G. , Jackson Matthew A. , Jaddoe Vincent W.V. , Joossens Marie , Jørgensen Torben , Keszthelyi Daniel , Knight Rob , Laakso Markku , Laudes Matthias , Launer Lenore J. , Lieb Wolfgang , Lusis Aldons J. , Masclee Ad A.M. , Moll Henriette A. , Mujagic Zlatan , Qibin Qi , Rothschild Daphna , Shin Hocheol , Sørensen Søren J. , Steves Claire J. , Thorsen Jonathan , Timpson Nicholas J. , Tito Raul Y. , Vieira-Silva Sara , Völker Uwe , Völzke Henry , Võsa Urmo , Wade Kaitlin H. , Walter Susanna , Watanabe Kyoko , Weiss Stefan , Weiss Frank U. , Weissbrod Omer , Westra Harm-Jan , Willemsen Gonneke , Payami Haydeh , Jonkers Daisy M.A.E. , Vasquez Alejandro Arias , de Geus Eco J.C. , Meyer Katie A. , Stokholm Jakob , Segal Eran , Org Elin , Wijmenga Cisca , Kim Hyung-Lae , Kaplan Robert C. , Spector Tim D. , Uitterlinden Andre G. , Rivadeneira Fernando , Franke Andre , Lerch Markus M. , Franke Lude , Sanna Serena , D’Amato Mauro , Pedersen Oluf , Paterson Andrew D. , Kraaij Robert , Raes Jeroen , Zhernakova Alexandra
Published: June 2020

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P<5×10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association withBifidobacteriumabundance. Other associations were suggestive (1.95×10−10<P<5×10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.
Growth impacts in a changing ocean: insights from two coral reef fishes in an extreme environment
Authors: D’Agostino Daniele , Burt John A. , Santinelli Veronica , Vaughan Grace O. , Fowler Ashley , Reader Tom , Taylor Brett M. , Hoey Andrew S. , Cavalcante Georgenes H. , Bauman Andrew G. , Feary David A.
Published: June 2020

Determining the life history consequences for fishes living in extreme and variable environments will be vital in predicting the likely impacts of ongoing climate change on reef fish demography. Here, we compare size-at-age and maximum body size of two common reef fish species (Lutjanus ehrenbergiiandPomacanthus maculosus) between the environmentally extreme Arabian/Persian Gulf (‘Arabian Gulf’) and adjacent comparably benign Oman Sea. Additionally, we use otolith increment width profiles to investigate the influence of temperature, salinity and productivity on the individual growth rates. Individuals of both species showed smaller size-at-age and lower maximum size in the Arabian Gulf compared to conspecifics in the less extreme and less variable environment of the Oman Sea, suggesting a life-history trade-off between size and metabolic demands. Salinity was the best environmental predictor of interannual growth across species and regions, with low growth corresponding to more saline conditions. However, salinity had a weaker negative effect on interannual growth of fishes in the Arabian Gulf than in the Oman Sea, indicating Arabian Gulf populations may be better able to acclimate to changing environmental conditions. Temperature had a weak positive effect on the interannual growth of fishes in the Arabian Gulf, suggesting that these populations may still be living within their thermal windows. Our results highlight the potential importance of osmoregulatory cost in impacting growth, and the need to consider the effect of multiple stressors when investigating the consequences of future climate change on fish demography.
Dynamics of isoflurane-induced vasodilation and blood flow of cerebral vasculature revealed by multi-exposure speckle imaging
Authors: Sullender Colin T. , Richards Lisa M. , He Fei , Luan Lan , Dunn Andrew K.
Published: June 2020

Background

Anesthetized animal models are used extensively during neurophysiological and behavioral studies despite systemic effects from anesthesia that undermine both accurate interpretation and translation to awake human physiology. The majority of work examining the impact of anesthesia on cerebral blood flow (CBF) has been restricted to before and after measurements with limited spatial resolution.

New Method

We used multi-exposure speckle imaging (MESI), an advanced form of laser speckle contrast imaging (LSCI), to characterize the dynamics of isoflurane anesthesia induction on cerebral vasculature and blood flow in the mouse brain.

Results

The large anatomical changes caused by isoflurane are depicted with wide-field imagery and video highlighting the induction of general anesthesia. Within minutes of exposure, both vessel diameter and blood flow increased drastically compared to the awake state and remained elevated for the duration of imaging. An examination of the dynamics of anesthesia induction reveals that blood flow increased faster in arteries than in veins or parenchyma regions.

Comparison with Existing Methods

MESI offers robust hemodynamic measurements across large fields-of-view and high temporal resolutions sufficient for continuous visualization of cerebrovascular events featuring major changes in blood flow.

Conclusion

The large alterations caused by isoflurane anesthesia to the cortical vasculature and CBF are readily characterized using MESI. These changes are unrepresentative of normal physiology and provide further evidence that neuroscience experiments would benefit from transitioning to un-anesthetized awake animal models.
A facile Q-RT-PCR assay for monitoring SARS-CoV-2 growth in cell culture
Authors: Mugisha Christian Shema , Vuong Hung R. , Puray-Chavez Maritza , Kutluay Sebla B.
Published: June 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the ongoing COVID-19 pandemic, has infected millions within just a few months and is continuing to spread around the globe causing immense respiratory disease and mortality. Assays to monitor SARS-CoV-2 growth depend on time-consuming and costly RNA extraction steps, hampering progress in basic research and drug development efforts. Here we developed a facile Q-RT-PCR assay that bypasses viral RNA extraction steps and can monitor SARS-CoV-2 replication kinetics from a small amount of cell culture supernatants. Using this assay, we screened the activities of a number of entry, SARS-CoV-2- and HIV-1-specific inhibitors in a proof of concept study. In line with previous studies which has shown that processing of the viral Spike protein by cellular proteases and endosomal fusion are required for entry, we found that E64D and apilimod potently decreased the amount of SARS-CoV-2 RNA in cell culture supernatants with minimal cytotoxicity. Surprisingly, we found that macropinocytosis inhibitor EIPA similarly decreased viral RNA in supernatants suggesting that entry may additionally be mediated by an alternative pathway. HIV-1-specific inhibitors nevirapine (an NNRTI), amprenavir (a protease inhibitor), and ALLINI-2 (an allosteric integrase inhibitor) modestly inhibited SARS-CoV-2 replication, albeit the IC50values were much higher than that required for HIV-1. Taken together, this facile assay will undoubtedly expedite basic SARS-CoV-2 research, be amenable to mid-throughput screens to identify chemical inhibitors of SARS-CoV-2, and be applicable to a broad number of RNA and DNA viruses.

Importance

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the COVID-19 pandemic, has quickly become a major global health problem causing immense respiratory disease and social and economic disruptions. Conventional assays that monitor SARS-CoV-2 growth in cell culture rely on costly and time-consuming RNA extraction procedures, hampering progress in basic SARS-CoV-2 research and development of effective therapeutics. Here we developed a facile Q-RT-PCR assay to monitor SARS-CoV-2 growth in cell culture supernatants that does not necessitate RNA extraction, and is as accurate and sensitive as existing methods. In a proof-of-concept screen, we found that E64D, apilimod, EIPA and remdesivir can substantially impede SARS-Cov-2 replication providing novel insight into viral entry and replication mechanisms. This facile approach will undoubtedly expedite basic SARS-CoV-2 research, be amenable to screening platforms to identify therapeutics against SARS-CoV-2 and can be adapted to numerous other RNA and DNA viruses.
Caudal-rostral progression of alpha motoneurone degeneration in the SOD1G93Amouse model of amyotrophic lateral sclerosis
Authors: Kirby Alastair J , Palmer Thomas , Mead Richard , Ichiyama Ronaldo , Chakrabarty Samit
Published: June 2020

Mice with transgenic expression of human SOD1G93Aare a widely used model of ALS, with a caudal-rostral progression of motor impairment. Previous studies have quantified the progression of motoneurone (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93Amice, to investigate whether there is a caudal-rostral progression of MN death. By 3-months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3-months the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord, in SOD1G93Amice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4-months of age. These findings agree with the corticofugal synaptopathy model, that α-MN and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1G93Amice. Hence, there is spatial and temporal caudal-rostral progression of α-MN and CST degeneration in SOD1G93Amice.

Highlights

SOD1G93Amice display a caudal-rostral progression of motor impairment.

Lumbar spinal cord of SOD1G93Amice has an enhanced susceptibility to degeneration.

SOD1G93Amice exhibit a caudal-rostral progression of α-MN and CST degeneration
Integrate Structural Analysis, Isoform Diversity, and Interferon-Inductive Propensity of ACE2 to Refine SARS-CoV2 Susceptibility Prediction in Vertebrates
Authors: Sang Eric R. , Tian Yun , Gong Yuanying , Miller Laura C. , Sang Yongming
Published: June 2020

The current new coronavirus disease (COVID-19) has caused globally near 0.4/6 million confirmed deaths/infected cases across more than 200 countries. As the etiological coronavirus (a.k.a. SARS-CoV2) may putatively have a bat origin, our understanding about its intermediate reservoir between bats and humans, especially its tropism in wild and domestic animals, are mostly unknown. This constitutes major concerns in public health for the current pandemics and potential zoonosis. Previous reports using structural analysis of the viral spike protein (S) binding its cell receptor of angiotensin-converting enzyme 2 (ACE2), indicate a broad SARS-CoV2 susceptibility in wild and particularly domestic animals. Through integration of key immunogenetic factors, including the existence of S-binding-void ACE2 isoforms and the disparity of ACE2 expression upon early innate immune response, we further refine the SARS-CoV2 susceptibility prediction to fit recent experimental validation. In addition to showing a broad susceptibility potential across mammalian species based on structural analysis, our results also reveal that domestic animals including dogs, pigs, cattle and goats may evolve ACE2-related immunogenetic diversity to restrict SARS-CoV2 infections. Thus, we propose that domestic animals may be unlikely to play a role as amplifying hosts unless the virus has further species-specific adaptation. These findings may relieve relevant public concerns regarding COVID-19-like risk in domestic animals, highlight virus-host coevolution, and evoke disease intervention through targeting ACE2 molecular diversity and interferon optimization.
Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay
Authors: Brannon A. Rose , Jayakumaran Gowtham , Diosdado Monica , Patel Juber , Razumova Anna , Hu Yu , Meng Fanli , Haque Mohammad , Sadowska Justyna , Murphy Brian J. , Baldi Tessara , Johnson Ian , Ptashkin Ryan , Hasan Maysun , Srinivasan Preethi , Rema Anoop Balakrishnan , Rijo Ivelise , Agarunov Aaron , Won Helen , Perera Dilmi , Brown David N. , Samoila Aliaksandra , Jing Xiaohong , Gedvilaite Erika , Yang Julie L. , Stephens Dennis P. , Dix Jenna-Marie , DeGroat Nicole , Nafa Khedoudja , Syed Aijazuddin , Li Alan , Lebow Emily S. , Bowman Anita S. , Ferguson Donna C. , Liu Ying , Mata Douglas A. , Sharma Rohit , Yang Soo-Ryum , Bale Tejus , Benhamida Jamal K. , Chang Jason C. , Dogan Snjezana , Hameed Meera R. , Hechtman Jaclyn F. , Moung Christine , Ross Dara S. , Vakiani Efsevia , Vanderbilt Chad M. , Yao JinJuan , Razavi Pedram , Smyth Lillian M. , Chandarlapaty Sarat , Iyer Gopa , Abida Wassim , Harding James J. , Krantz Benjamin , O’Reilly Eileen , Yu Helena A. , Li Bob , Rudin Charles , Diaz Luis , Solit David B. , Arcila Maria E. , Ladanyi Marc , Houck-Loomis Brian , Tsui Dana , Berger Michael F. , Zehir Ahmet , Benayed Ryma
Published: June 2020

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 98% fora priorimutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.
Segmenting surface boundaries using luminance cues: Underlying mechanisms
Authors: DiMattina Christopher , Baker Curtis L.
Published: June 2020

Segmenting scenes into distinct surfaces is a basic visual perception task, and luminance differences between adjacent surfaces often provide an important segmentation cue. However, mean luminance differences between two surfaces may exist without any sharp change in albedo at their boundary, but rather from differences in the proportion of small light and dark areas within each surface, e.g. texture elements, which we refer to as aluminance texture boundary. Here we investigate the performance of human observers segmenting luminance texture boundaries. We demonstrate that a simple model involving a single stage of filtering cannot explain observer performance, unless it incorporates contrast normalization. Performing additional experiments in which observers segment luminance texture boundaries while ignoring super-imposed luminance step boundaries, we demonstrate that the one-stage model, even with contrast normalization, cannot explain performance. We then present a Filter-Rectify-Filter (FRF) model positing two cascaded stages of filtering, which fits our data well, and explains observers’ ability to segment luminance texture boundary stimuli in the presence of interfering luminance step boundaries. We propose that such computations may be useful for boundary segmentation in natural scenes, where shadows often give rise to luminance step edges which do not correspond to surface boundaries.
Presence of Live SARS-CoV-2 Virus in Feces of Coronavirus Disease 2019 (COVID-19) Patients: A Rapid Review
Authors: Sehmi Prabjot , Cheruiyot Isaac
Published: June 2020

Coronavirus disease 2019 (COVID-19) is a rapidly escalating pandemic that has spread to many parts of the world. The disease has already affected over 6 million individuals, with over 400,000 fatalities. Recent studies have confirmed the presence of SARS-CoV-2 nucleic acids in feces of Coronavirus disease 2019 (COVID-19) patients using RT-PCR tests. It is however, still unclear as to whether or not live SARS-CoV-2 virus is actually present in feces of these patients. In this rapid review, we systematically analyzed literature to establish any evidence of live SARS-CoV- 2 virus in fecal samples of COVID-19 patients. We identified 4 studies (one case report, 2 case series and 1 cohort study) where the SARS-CoV-2 was successfully isolated from fecal samples of COVID-19 patients using culture techniques. Therefore, there is some evidence COVID-19 could shed live SARS-CoV-2 virus via the gastro-intestinal tract. Larger studies are needed to corroborate these findings, as well as to determine its potential for disease transmission and infection, and possible implications for COVID-19 discharge and isolation policies.
Chest CT Images for COVID-19: Radiologists and Computer-based detection
Authors: Dou Qingli , Liu Jiangping , Zhang Wenwu , Gu Yanan , Hsu Wan-Ting , Ho Kuan-Ching , Tong Hoi Sin , Yu Wing Yan , Lee Chien-Chang
Published: June 2020

Background

Characteristic chest computed tomography (CT) manifestation of 2019 novel coronavirus (COVID-19) was added as a diagnostic criterion in the Chinese National COVID-19 management guideline. Whether the characteristic findings of Chest CT could differentiate confirmed COVID-19 cases from other positive nucleic acid test (NAT)-negative patients has not been rigorously evaluated.

Purpose

We aim to test whether chest computed tomography (CT) manifestation of 2019 novel coronavirus (COVID-19) can be differentiated by a radiologist or a computer-based CT image analysis system.

Methods

We conducted a retrospective case-control study that included 52 laboratory-confirmed COVID-19 patients and 80 non-COVID-19 viral pneumonia patients between 20 December, 2019 and 10 February, 2020. The chest CT images were evaluated by radiologists in a double blind fashion. A computer-based image analysis system (uAI system, Lianying Inc., Shanghai, China) detected the lesions in 18 lung segments defined by Boyden classification system and calculated the infected volume in each segment. The number and volume of lesions detected by radiologist and computer system was compared with Chi-square test or Mann-Whitney U test as appropriate.

Results

The main CT manifestations of COVID-19 were multi-lobar/segmental peripheral ground-glass opacities and patchy air space infiltrates. The case and control groups were similar in demographics, comorbidity, and clinical manifestations. There was no significant difference in eight radiologist identified CT image features between the two groups of patients. There was also no difference in the absolute and relative volume of infected regions in each lung segment.

Conclusions

We documented the non-differentiating nature of initial chest CT image between COVID-19 and other viral pneumonia with suspected symptoms. Our results do not support CT findings replacing microbiological diagnosis as a critical criterion for COVID-19 diagnosis. Our findings may prompt re-evaluation of isolated patients without laboratory confirmation.
Diffuse white matter abnormality in very preterm infants reflects reduced brain network efficiency
Authors: Kline Julia E. , Priyanka Illapani Venkata Sita , Li Hailong , He Lili , Parikh Nehal A.
Published: June 2020

Between 50-80% of very preterm infants (≤32 weeks gestational age) exhibit increased white matter signal intensity on T2 MRI at term-equivalent age, known as diffuse white matter abnormality (DWMA). A few studies have linked DWMA with microstructural abnormalities, but the exact relationship remains poorly understood. We used graph theory methods to relate DWMA extent to measures of efficient information processing at term in a representative cohort of 343 very preterm infants. We performed anatomic and diffusion MRI at term and quantified DWMA volume using our novel, semi-automated algorithm. From structural connectomes, we calculated graph theory metrics: local efficiency and clustering coefficient, which measure the ability of groups of nodes to perform specialized processing, and global efficiency, which assesses the ability of brain regions to efficiently combine information. We computed partial correlations between these measures and DWMA volume, adjusted for confounders. Increasing DWMA volume was associated with decreased global efficiency of the entire brain network (r= - 0.27, p= 8.36E-07) and decreased local efficiency and clustering coefficient within individual networks supporting cognitive, linguistic, and motor functions. We show that DWMA is associated with widespread decreased brain network connectivity in very preterm infants, suggesting it is pathologic and likely has adverse developmental consequences.
Evaluation of national responses to COVID-19 pandemic based on Pareto optimality
Authors: Kochańczyk Marek , Lipniacki Tomasz
Published: June 2020

Countries worldwide have adopted various strategies to minimize the socio-economic impact of the ongoing COVID-19 pandemic. Stringency and efficacy of imposed measures vary due to diversity of organizational cultures and ingrained societal practices, but also universally reflect the standpoint from which protecting public health and saving economy are seen as contradictory objectives. We analyzed cumulative deaths per capita and cumulative mobility reduction related to the decrease of economic activity in terms of Pareto optimality to show that as long as epidemic suppression is the aim, the trade-off between the death toll and economic loss is illusory: high death toll correlates with deep lockdown and thus, very likely, with severe economic downturn. We explained this effect by analyzing national epidemic trajectories in the mobility reduction vs. reproduction number (R) plane. When the number of daily new infections is high, mobility reduction is the only way to bring R below 1, but when new infections become sporadic, the epidemic can be suppressed by efficient testing complemented by relatively mild restrictions. South American trajectories suggest that lifting mobility restrictions at R > 1 may ultimately lead to the “herd immunity scenario”, in which transient lockdown only adds economic costs to an inevitably high death toll.
Mesoscopic cortical network reorganization during recovery of partial optic nerve injury in GCaMP6s mice
Authors: Groleau Marianne , Nazari-Ahangarkolaee Mojtaba , Vanni Matthieu P. , Higgins Jacqueline L. , Vézina Bédard Anne-Sophie , Sabel Bernhard A. , Mohajerani Majid H. , Vaucher Elvire
Published: June 2020

As the residual vision following a traumatic optic nerve injury can spontaneously recover over time, we explored the plasticity of cortical networks during the early post-optic nerve crush (ONC) phase. Usingin vivowide-field calcium imaging on awake Thy1-GCaMP6s mice, we characterized resting state and evoked cortical activity before, during, and 30 days after ONC. The recovery of monocular visual acuity and depth perception was evaluated at the same time points. Cortical responses to an LED flash decreased in the contralateral hemisphere in the primary visual cortex and in the secondary visual areas following the ONC, but was partially rescued between 3 and 5 days post-ONC, remaining stable thereafter. The connectivity between visual and non-visual regions was disorganized after the crush, as shown by a decorrelation, but correlated activity was restored 30 days after the injury. The number of surviving retinal ganglion cells dramatically dropped and remained low. At the behavioral level, the ONC resulted in visual acuity loss on the injured side and an increase in visual acuity with the non-injured eye. In conclusion, our results show a reorganization of connectivity between visual and associative cortical areas after an ONC, which is indicative of spontaneous cortical plasticity.
Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior inDrosophila melanogaster
Authors: Olivares Gonzalo H. , Núñez-Villegas Franco , Candia Noemi , Oróstica Karen , Vega-Macaya Franco , Zúñiga Nolberto , Molina Cristian , Mackay Trudy F. C. , Verdugo Ricardo A. , Olguín Patricio
Published: June 2020

The mechanisms by which the genotype interacts with nutrition during development to contribute to the variation of complex behaviors and brain morphology of adults are not well understood. Here we use theDrosophilaGenetic Reference Panel to identify genes and pathways underlying these interactions in sleep behavior and mushroom body morphology. We show that early-life nutritional restriction has genotype-specific effects on variation in sleep behavior and brain morphology. We mapped genes associated with sleep sensitivity to early-life nutrition, which were enriched for protein-protein interactions responsible for translation, endocytosis regulation, ubiquitination, lipid metabolism, and neural development. By manipulating the expression of candidate genes in the mushroom bodies and all neurons, we confirm that genes regulating neural development, translation and insulin signaling contribute to the variable response of sleep and brain morphology to early-life nutrition. We show that the interaction between differential expression of candidate genes with nutritional restriction in early life resides in the mushroom bodies or other neurons, and that these effects are sex specific. Natural variation in genes that control the systemic response to nutrition and brain development and function interact with early-life nutrition in different types of neurons to contribute to the variation of brain morphology and adult sleep behavior.
The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome
Authors: Ferro Iolanda , Gavini Jacopo , Bracher Lisamaria , Landolfo Marc , Candinas Daniel , Stroka Deborah , Polacek Norbert
Published: June 2020

The small non-coding vault RNA (vtRNA) 1-1 has been shown to confer apoptosis resistance in several malignant cell lines and also to modulate the autophagic flux in hepatocytes, thus highlighting its pro-survival role. Here we describe a new function of vtRNA1-1 in regulatingin vitroandin vivotumor cell proliferation, tumorigenesis and chemoresistance. By activating extracellular signal-regulated kinases (ERK 1/2), vtRNA1-1 knock-out (KO) inhibits transcription factor EB (TFEB), leading to a downregulation of the coordinated lysosomal expression and regulation (CLEAR) network genes and lysosomal compartment dysfunction. Pro-tumorigenic pathways dysregulation and decreased lysosome functionality potentiate the anticancer effect of conventional targeted cancer drugs in the absence of vtRNA1-1. Finally, vtRNA1-1 KO-reduced lysosomotropism, together with a higher intracellular compound availability, significantly reduced tumor cell proliferationin vitroandin vivo. These findings reveal the role of vtRNA1-1 in ensuring intracellular catabolic compartment stability and functionality, suggesting its importance in lysosome-mediated chemotherapy resistance.
No Assembly Required: Using BTyper3 to Assess the Congruency of a Proposed Taxonomic Framework for the Bacillus cereus group with Historical Typing Methods
Authors: Carroll Laura M. , Cheng Rachel A. , Kovac Jasna
Published: June 2020

The Bacillus cereus group, also known as B. cereus sensu lato (s.l.), is a species complex comprising numerous closely related lineages, which vary in their ability to cause illness in humans and animals. The classification of B. cereus s.l. isolates into species-level taxonomic units is essential for facilitating communication between and among microbiologists, clinicians, public health officials, and industry professionals, but is not always straightforward. A recently proposed genomospecies-subspecies-biovar taxonomic framework aims to provide a standardized nomenclature for this species complex but relies heavily on whole-genome sequencing (WGS), a technology with limited accessibility. It thus is unclear whether popular, low-cost typing methods (e.g., single- and multi-locus sequence typing) remain congruent with the proposed taxonomy. Here, we characterize 2,231 B. cereus s.l. genomes using a combination of in silico (i) average-nucleotide identity (ANI)-based genomospecies assignment, (ii) ANI-based subspecies assignment, (iii) seven-gene multi-locus sequence typing (MLST), (iv) panC group assignment, (v) rpoB allelic typing, and (vi) virulence factor detection. We show that sequence types (STs) assigned using MLST can be used for genomospecies assignment, and we provide a comprehensive list of ST/genomospecies associations. For panC group assignment, we show that an adjusted, eight-group framework is largely congruent with the proposed eight-genomospecies taxonomy and resolves incongruencies observed in the historical seven-group framework among isolates assigned to panC Groups II, III, and VI. We additionally provide a list of loci that capture the topology of the whole-genome B. cereus s.l. phylogeny that may be used in future sequence typing efforts. For researchers with access to WGS, MLST, and/or panC data, we showcase how our recently released software, BTyper3 (https://github.com/lmc297/BTyper3), can be used to assign B. cereus s.l. isolates to taxonomic units within this proposed framework with little-to-no user intervention or domain-specific knowledge of B. cereus s.l. taxonomy. We additionally outline a novel method for assigning B. cereus s.l. genomes to pseudo-gene flow units within proposed genomospecies. The results presented here highlight the backwards-compatibility and accessibility of the proposed taxonomic framework and illustrate that WGS is not a necessity for microbiologists who want to use the proposed taxonomy effectively.
Mps1 promotes poleward chromosome movements in meiotic pro-metaphase
Authors: Meyer Régis E , Tipton Aaron R , Gorbsky Gary J , Dawson Dean S
Published: June 2020

In prophase of meiosis I, homologous partner chromosomes pair and become connected by crossovers. Chiasmata, the connections formed between the partners enable the chromosome pair, called a bivalent, to attach as a single unit to the spindle. When the meiosis I spindle forms in prometaphase, most bivalents are associated with a single spindle pole and go through a series of oscillations on the spindle, attaching to and detaching from microtubules until the partners of the bivalent are bi-oriented, that is, attached to microtubules from opposite sides of the spindle, and prepared to be segregated at anaphase I. The conserved, kinetochore-associated kinase, Mps1, is essential for the bivalents to be pulled by microtubules across the spindle in prometaphase. Here we show thatMPS1is not required for kinetochores to attach microtubules but instead is necessary to trigger the migration of microtubule-attached kinetochores towards the poles. Our data support the model that Mps1 triggers depolymerization of microtubule ends once they attach to kinetochores in prometaphase. Thus, Mps1 acts at the kinetochore to co-ordinate the successful attachment of a microtubule and the triggering of microtubule depolymerization to move the chromosome.
Initial spindle positioning at the oocyte center protects against incorrect kinetochore-microtubule attachment and aneuploidy in mice
Authors: Kincade Jessica N. , Hlavacek Avery , Akera Takashi , Balboula Ahmed Z.
Published: June 2020

Spindle positioning within the oocyte must be regulated tightly. Following nuclear envelope breakdown (NEBD), the spindle is predominantly assembled at the oocyte center prior to its migration towards the cortex to achieve the highly asymmetric division, a characteristic of female meiosis. The significance of the initial central positioning of the spindle is largely unknown. Here we show that the centered spindle in mouse oocytes is an insurance mechanism to avoid the premature exposure to cortical CDC42 signaling, which perturbs proper kinetochore-microtubule attachments, leading to the formation of aneuploid gametes. Because the spindle forms where NEBD occurs, nucleus position significantly influences the location of the initial spindle assembly. We also find that this nucleus positioning is a dynamic process that depends on maternal age. These findings will help in understanding why female gametes are notoriously associated with high rates of aneuploidy, the leading genetic cause of miscarriage and congenital abnormalities.
The fast and superprocessive KIF1A predominately resides in a vulnerable one-head-bound state during its chemomechanical cycle
Authors: Zaniewski Taylor M. , Gicking Allison M. , Fricks John , Hancock William O.
Published: June 2020

Kinesin-3 are the fastest and most processive motors of the three neuronal transport kinesin families, yet the sequence of states and rates of kinetic transitions that comprise the chemomechanical cycle are poorly understood. We used stopped-flow fluorescence spectroscopy and single-molecule motility assays to delineate the chemomechanical cycle of the kinesin-3, KIF1A. Our bacterially expressed KIF1A construct, dimerized via a kinesin-1 coiled-coil, exhibits fast velocity and superprocessivity behavior similar to wild-type KIF1A. We established that the KIF1A forward step is triggered by hydrolysis of ATP and not by ATP binding, meaning that KIF1A follows the same chemomechanical cycle as established for kinesin-1 and-2. The ATP-triggered half-site release rate of KIF1A was similar to the stepping rate, indicating that during stepping, rear-head detachment is an order of magnitude faster than in kinesin-1 and kinesin-2. Thus, KIF1A spends the majority of its hydrolysis cycle in a one-head-bound state. Both the ADP off-rate and the ATP on-rate at physiological ATP concentration were fast, eliminating these steps as possible rate limiting transitions. Based on the measured run length and the relatively slow off-rate in ADP, we conclude that attachment of the tethered head is the rate limiting transition in the KIF1A stepping cycle. The fast speed, superprocessivity and load sensitivity of KIF1A can be explained by a fast rear head detachment rate, a rate-limiting step of tethered head attachment that follows ATP hydrolysis, and a relatively strong electrostatic interaction with the microtubule in the weakly-bound post-hydrolysis state.
Exploring Bottom-Up Visual Processing and Visual Hallucinations in Parkinson’s Disease with Dementia
Authors: Murphy Nicholas , Killen Alison , Graziadio Sara , Rochester Lynn , Firbank Michael , Baker Mark R , Allan Charlotte , Collerton Daniel , Taylor John-Paul , Urwyler Prabitha
Published: June 2020

Visual hallucinations (VH) are a common symptom of Parkinson’s disease with dementia (PDD), affecting up to 65% of cases. Integrative models of their etiology posit that a decline in executive control of the visuo-perceptual system is a primary mechanism of VH generation. The role of bottom-up processing in the manifestation of VH in this condition is still not clear. Here we compared amplitude and latency patterns of reversal visual evoked potentials (VEPs) in healthy controls (n=21) and PDD patients (n = 34) with a range of VH severities. PDD patients showed increased N2 latency relative to controls, but patients reporting complex VH (n=17) did not demonstrate any relationship between VEP measurements and their hallucination severity as measured on the neuropsychiatric inventory hallucinations subscale (NPIHal) score. Our VEP findings support previous reports of declining visual system physiology in PDD. However, no notable major relationships between the integrity of the visual pathway and VH were found.