bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 experience: first Italian survey on healthcare staff members from a Mother-Child Research Hospital using combined molecular and rapid immunoassays test
Authors: Comar Manola , Brumat Marco , Concas Maria Pina , Argentini Giorgia , Bianco Annamonica , Bicego Livia , Bottega Roberta , Carli Petra , Cassone Andrea , Catamo Eulalia , Cocca Massimiliano , Del Pin Massimo , Di Stazio Mariateresa , Feresin Agnese , Bianca Martina La , Morassut Sara , Morgan Anna , Pelliccione Giulia , Petix Vincenzo , Ragusa Giulia , Robino Antonietta , Russian Stefano , Spedicati Beatrice , Suergiu Sarah , Urriza Marianela , Vascotto Fulvia , Toscani Paola , Girotto Giorgia , Gasparini Paolo
Published: April 2020

The fast spread of the novel coronavirus (SARS-CoV-2) has become a global threat hitting the worldwide fragile health care system. In Italy, there is a continued COVID-19 growth of cases and deaths that requires control measures for the correct management of the epidemiological emergency. To contribute to increasing the overall knowledge of COVID-19, systematic tests in the general population are required.

Here, we describe the first Italian survey performed in 727 employees belonging to a Mother-Child Research hospital tested for both viral (nasopharyngeal and oropharyngeal swabs) and antibody presence. Individuals were divided into three risk categories (high, medium and low) according to their job activity. Only one subject was positive at the swab test while 17.2% of the cohort was positive for the presence of antibodies. Results highlighted that the presence of Positive antibodies is significantly associated with high and medium risk exposure occupation (p-value=0.026) as well as cold and conjunctivitis symptoms (p-value=0.016 and 0.042 respectively). Moreover, among healthcare professionals, the category of medical doctors showed a significant association with the presence of antibodies against SARS-CoV-2 (p-value=0.0127). Finally, we detected a rapid decrease in antibody intensity between two assessments performed within a very short period (p-value=0.009). Overall, the present study increases our knowledge of the epidemiological data of COVID-19 infection in Italy, suggesting a high prevalence of immune individuals (i.e. at least among at-risk categories) and the efficacy of the combined diagnostic protocol to monitor the possible outbreak.
COVID-19 Outbreak in Post-Soviet States: Modeling the Best and Worst Possible Scenarios
Authors: Issanov Alpamys , Amanbek Yerlan , Abbay Anara , Adambekov Shalkar , Aljofan Mohamad , Kashkynbayev Ardak , Gaipov Abduzhappar
Published: April 2020

Background

COVID-19 pandemic has presented extreme challenges to developing countries across the world. Post-Soviet states are facing unique challenges due to their developing healthcare systems and unstable economy. The aim of this paper was to provide estimates for current development COVID-19 pandemic in the Post-Soviet states and forecast potential best and worst scenarios for spread of this deadly infection.

Methods

The data on confirmed cases and deaths were extracted from official governmental sources for a period from beginning of outbreak dates for each country until April 18, 2020. A modified SEIR (Susceptible-Exposed-Infected-Recovered) modelling was used to plot the parameters of epidemic in 10 post-Soviet states and forecast the number of cases over a period of 10, 30 and 60 days. We also estimated the numbers of cases based on the optimal measures (best scenario) and suboptimal measures (worst scenarios) of potential spread of COVID-19 in these countries.

Results

It was estimated that Armenia and Azerbaijan have reached their peaks, Kazakhstan, Kyrgyzstan, Moldova and Uzbekistan are expected to reach their peaks in the coming week (April 29 – May 7, 2020), with comparatively low cases of COVID-19 and loss of lives in the best-case scenario. In contrast, Belarus, Russia, and Ukraine would likely see the outbreaks with the largest number of COVID-19 cases amongst the studied Post-Soviet States in the worst scenario during the next 30 and 60 days. Geographical remoteness and small number of international travelers from the countries heavily affected by the pandemic could also have contributed to delay in the spread of COVID-19.

Conclusion

Governmental response was shown to be as an important determining factor responsible for the development of COVID-19 epidemic in Post-Soviet states. The current protection rates should be maintained to reduce active cases during upcoming 30 and 60 days. The estimated possible scenarios based on the proposed model can potentially be used by healthcare professionals from each studied Post-Soviet States as well as others to improve plans to contain the current and future epidemic.
Influence of blood pressure on pneumonia risk: Epidemiological association and Mendelian randomisation in the UK Biobank
Authors: Zekavat Seyedeh M. , Honigberg Michael , Pirruccello James , Kohli Puja , Karlson Elizabeth W. , Newton-Cheh Christopher , Zhao Hongyu , Natarajan Pradeep
Published: April 2020

Objectives

To determine whether elevated blood pressure influences risk for respiratory infection.

Design

Prospective, population-based epidemiological and Mendelian randomisation studies.

Setting

UK Biobank.

Participants

377,143 self-identified British descent (54% women; median age 58 years) participants in the UK Biobank.

Main outcome measures

First incident pneumonia over an average of 8 follow-up years.

Results

107,310 (30%) participants had hypertension at UK Biobank enrolment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension at baseline was significantly associated with increased risk for incident respiratory disease including pneumonia (hazard ratio 1.36 (95% confidence interval 1.29 to 1.43), P<0.001), acute respiratory distress syndrome or respiratory failure (1.43 (1.29 to 1.59), P<0.001), and chronic lower respiratory disease (1.30 (1.25 to 1.36), P<0.001), independent of age, age2, sex, smoking status, BMI, prevalent diabetes mellitus, prevalent coronary artery disease, and principal components of ancestry. Mendelian randomisation analyses indicated that genetic predisposition to a 5 mmHg increase in blood pressure was associated with increased risk of incident pneumonia for SBP (1.08, (1.04 to 1.13), P<0.001) and DBP (1.11 (1.03 to 1.20), P=0.005). Additionally, consistent with epidemiologic associations, increase in blood pressure genetic risk was significantly associated with reduced forced expiratory volume in the first second, forced vital capacity, and the ratio of the two (P<0.001 for all).

Conclusions

These results strongly suggest that elevated blood pressure independently increases risk for pneumonia and reduces pulmonary function. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Whether the present findings are generalizable to novel coronavirus disease 2019 (COVID-19) require further study.

Summary Box

Section 1: What is already known on this topic

Hypertension has been associated with pneumonia in small observational studies.

Based on early epidemiologic analyses, hypertension is described as a risk factor for SARS-CoV-2 infection and associated novel coronavirus disease 2019 (COVID-19).

The influence of hypertension on pneumonia risk is difficult to assess in traditional observational studies.

Section 2: What this study adds

Our pre-COVID-19 analyses are consistent with a causal relationship between increased blood pressure and increased risk for incident respiratory infections, as well as between increased blood pressure and reduced pulmonary function.

These results support hypertension as a pneumonia risk factor; efforts to optimize blood pressure may reduce risk for pneumonia.
A semi-analytic elastic rod model of pediatric spinal deformity
Authors: Neelakantan Sunder , Purohit Prashant K. , Pasha Saba
Published: April 2020

The mechanism of the scoliotic curve development in healthy adolescents remains unknown in the field of orthopedic surgery. Variations in the sagittal curvature of the spine are believed to be a leading cause of scoliosis in this patient population. Here, we formulate the mechanics of S-shaped slender elastic rods as a model for pediatric spine under physiological loading. Secondarily, applying inverse mechanics to clinical data of the scoliotic spines, with characteristic 3D deformity, we determine the undeformed geometry of the spine before the induction of scoliosis. Our result successfully reproduces the clinical data of the deformed spine under varying loads confirming that the pre-scoliotic sagittal curvature of the spine impacts the 3D loading that leads to scoliosis.
Monitoring ligand-induced changes in receptor conformation with NanoBiT conjugated nanobodies
Authors: Soave Mark , Heukers Raimond , Kellam Barrie , Woolard Jeanette , Smit Martine J. , Briddon Stephen J. , Hill Stephen J.
Published: April 2020

Camelid single-domain antibody fragments (nanobodies) offer the specificity of an antibody in a single 15kDa immunoglobulin domain. Their small size allows for easy genetic manipulation of the nanobody sequence to incorporate protein tags, facilitating their use as biochemical probes. The nanobody VUN400, which recognises the second extracellular loop of the human CXCR4 chemokine receptor, was used as a probe to monitor specific CXCR4 conformations. VUN400 was fused via its C-terminus to the 11-amino acid HiBiT tag (VUN400-HiBiT) which complements to LgBiT protein, forming a full length functional NanoLuc luciferase. Here, complemented luminescence was used to detect VUN400-HiBiT binding to CXCR4 receptors expressed in living HEK293 cells. VUN400-HiBiT binding to CXCR4 could be prevented by orthosteric and allosteric ligands, allowing VUN400-HiBiT to be used as a probe to detect specific conformations of CXCR4. These data demonstrate that the high specificity offered by extracellular-targeted nanobodies can be utilised to probe receptor pharmacology.
Population genetics of sugar kelp in the Northwest Atlantic region using genome-wide markers
Authors: Mao Xiaowei , Augyte Simona , Huang Mao , Hare Matthew P. , Bailey David , Umanzor Schery , Marty-Rivera Michael , Robbins Kelly R , Yarish Charles , Lindell Scott , Jannink Jean-Luc
Published: April 2020

An assessment of genetic diversity of marine populations is critical not only for the understanding and preservation of natural biodiversity but also for its economic potential. As commercial demand rises for marine resources, it is critical to generate baseline information for monitoring wild populations. Furthermore, anthropogenic stressors on the coastal environment, such as warming sea surface temperatures and overharvesting of wild populations, are leading to the destruction of keystone marine species such as kelps. In this study, we conducted a fine-scale genetic analysis using genome-wide high-density markers on Northwest Atlantic sugar kelp species,Saccharina latissimaand putative species,Saccharina angustissima. The population structure for a total of 149 samples from the Gulf of Maine (GOM) and Southern New England (SNE) was investigated using AMOVA, Fst, admixture, and PCoA. Genome-wide association analyses were conducted for six morphological traits, and the extended Lewontin and Krakauer (FLK) test was used to detect selection signatures. Our results indicate that the GOM region is moderately more heterogeneous than SNE. While admixture was observed between regions, these results confirm that Cape Cod acts as a biogeographic barrier for sugar kelp gene flow. We detected one significant SNP (P-value=2.03×10−7) associated with stipe length, and 243 SNPs with higher-than-neutral differentiation. The findings of this study provide fundamental knowledge on sugar kelp population genetics for future monitoring, managing and potentially restoring wild populations, as well as assisting in selective breeding to improve desirable traits for cultivation and bioenergy production.
Bayesian neural networks for the optimisation of biological clocks in humans
Authors: Alfonso G , Gonzalez Juan R
Published: April 2020

DNA methylation is related to aging. Some researchers, such as Horvath or Levine have managed to create epigenetic and biological clocks that predict chronological age using methylation data. These authors used Elastic Net methodology to build age predictors that had a high prediction accuracy. In this article, we propose to improve their performance by incorporating an additional step using neural networks trained with Bayesian learning. We shown that this approach outperforms the results obtained when using Horvath’s method, neural networks directly, or when using other training algorithms, such as Levenberg-Marquardt’s algorithm. The R-squared value obtained when using our proposed approach in empirical (out-of sample) data was 0.934, compared to 0.914 when using a different training algorithm (Levenberg Marquard), or 0.910 when applying the neural network directly (e.g. without first reducing the dimensionality of the data). The results were also tested in independent datasets that were not used during the training phase. Our method obtained better R-squared values and RMSE than Horvath’s and Levine’s method in 8 independent datasets. We demonstrate that building an age predictor using a Bayesian based algorithm provides accurate age predictions. This method is implemented in an R function, which is available through a package created for predicting purposes and is applicable to methylation data. This will help to elucidate the role of DNA methylation age in complex diseases or traits related to aging.
Redesigned Reporter Gene for Improved Proton Exchange-based Molecular MRI Contrast
Authors: Perlman Or , Ito Hirotaka , Gilad Assaf A. , McMahon Michael T. , Chiocca E. Antonio , Nakashima Hiroshi , Farrar Christian T.
Published: April 2020

Reporter gene imaging allows for non-invasive monitoring of molecular processes in living cells, providing insights on the mechanisms underlying pathology and therapy. A lysine-rich protein (LRP) chemical exchange saturation transfer (CEST) MRI reporter gene has previously been developed and used to image tumor cells, cardiac viral gene transfer, and oncolytic virotherapy. However, the highly repetitive nature of the LRP reporter gene sequence leads to DNA recombination events and the expression of a range of truncated LRP protein fragments, thereby greatly limiting the CEST sensitivity. Here we report the use of a redesigned LRP reporter (rdLRP), aimed to provide excellent stability and CEST sensitivity. The rdLRP contains no DNA repeats or GC rich regions and 30% less positively charged amino-acids. RT-PCR of cell lysates transfected with rdLRP demonstrated a stable reporter gene with a single distinct band corresponding to full-length DNA. A distinct increase in CEST-MRI contrast was obtained in cell lysates of rdLRP transfected cells and inin vivoLRP expressing mouse brain tumors (p=0.0275, n=10).
Serpins: Purification and characterization of potent protease inhibitors fromClostridium thermocellum
Authors: Mushtaq Maria , Asad Muhammad Javaid , Hyder Muhammad Zeeshan , Naqvi Syed Muhammad Saqlan , Malik Saad Imran , Mehmood Raja Tahir
Published: April 2020

Clostridium thermocellumproduces an extracellular cellulosome (a multiprotein complex produced by firmicutes bacteria), which, owing to its extracellular location, is open to protease attack. Serine protease inhibitors (serpins) protect bacteria against protease attack. However, their structure and function are poorly characterized. This study identified and amplified the serpin 1270 gene from the C. thermocellum genome. Purified serpins were cloned into the pTXB1 vector using the one-step sequence and ligation-independent cloning reaction and transformed into Escherichia coli BL21 DE3 cells. Enzyme overexpression and purification and enzyme inhibitory assays were performed. The results showed that serpin 1270 has 89% inhibition against Bacillus subtilisin and 64% inhibition against trypsin, chymotrypsin, and papain.
Excitatory and inhibitory L2/3 neurons in mouse primary visual cortex are balanced in their input connectivity
Authors: Brown Alexander P.Y. , Cossell Lee , Margrie Troy W.
Published: April 2020

Quantitatively characterising brain-wide connectivity of neural circuits is of vital importance in understanding the function of the mammalian cortex. Here we have designed an analytical approach to examine data from hierarchical segmentation ontologies, and applied it in the comparison of long-range presynaptic connectivity onto excitatory and inhibitory neurons in layer 2/3 (L2/3) of mouse primary visual cortex (V1). We find that long-range connections onto these two general cell classes in L2/3 originate from highly similar brain regions, and in similar proportions, when compared to input to layer 6. These anatomical data suggest that distal information received by excitatory and inhibitory networks is highly homogenous in L2/3.
The Impact of Hand Movement Velocity on Cognitive Conflict Processing in a 3D Object Selection Task in Virtual Reality
Authors: Singh Avinash K , Gramann Klaus , Chen Hsiang-Ting , Lin Chin-Teng
Published: April 2020

Detecting and correcting incorrect body movements is an essential part of everyday interaction with one’s environment. The human brain provides a monitoring system that constantly controls and adjusts our actions according to our surroundings. However, when our brain’s predictions about a planned action do not match the sensory inputs resulting from that action, cognitive conflict occurs. Much is known about cognitive conflict in 1D/2D environments; however, less is known about the role of movement characteristics associated with cognitive conflict in 3D environment. Hence, we devised an object selection task in a virtual reality (VR) environment to test how the velocity of hand movements impacts human brain responses. From a series of analyses of EEG recordings synchronized with motion capture, we found that the velocity of the participants’ hand movements modulated the brain’s response to proprioceptive feedback during the task and induced a prediction error negativity (PEN). Additionally, the PEN originates in the anterior cingulate cortex and is itself modulated by the ballistic phase of the hand’s movement. These findings suggest that velocity is an essential component of integrating hand movements with visual and proprioceptive information during interactions with real and virtual objects.
Highly accurate random DNA sequencing using inherent interlayer potential traps of bilayer MoS2nanopores
Authors: Sen Payel , Hoi Hiofan , Nandi Dipanjan , Gupta Manisha
Published: April 2020

Solid-state MoS2nanopores are emerging as potential real-time DNA sequencers due to their ultra-thinness and pore stability. One of the major challenges in determining random nucleotide sequence (unlike polynucleotide strands) is the non-homogeneity of the charge interaction and velocity during DNA translocation. This results in varying blockade current for the same nucleotide, reducing the sequencing confidence. In this work, we studied the inherent impedance-tunability (due to vertical interlayer potential gradient and ion accumulation) of multilayered MoS2nanopores along with its effect on improving analyte capture and charge interaction, for more sensitive and confident sensing. Experimentally we demonstrate that 2-3 nm diameter bilayer MoS2pores are best suited for high accuracy (~90%) sequencing of mixed nucleotides with signal-to-noise-ratio greater than 11 in picomolar concentration solutions. High temporal resolution demonstrated by bilayer MoS2nanopores can help detect neutral proteins in future. The high accuracy detection in low concentration analyte can hence be applied for control and prevention of hereditary diseases and understanding health effects of rare microbial strains.
Network communication models improve the behavioral and functional predictive utility of the human structural connectome
Authors: Seguin Caio , Tian Ye , Zalesky Andrew
Published: April 2020

The connectome provides a structural substrate facilitating communication between brain regions. We aimed to establish whether accounting for polysynaptic communication paths in structural connectomes would improve prediction of interindividual variation in behavior as well as increase structure-function coupling strength. Structural connectomes were mapped for 889 healthy adults participating in the Human Connectome Project. To account for polysynaptic signaling, connectomes were transformed into communication matrices for each of 15 different network communication models. Communication matrices were (i) used to perform predictions of five data-driven behavioral dimensions and (ii) correlated to interregional resting-state functional connectivity (FC). While FC was the most accurate predictor of behavior, network communication models, in particular communicability and navigation, improved the performance of structural connectomes. Accounting for polysynaptic communication also significantly strengthened structure-function coupling, with the navigation and shortest paths models leading to 35-65% increases in association strength with FC. Combining behavioral and functional results into a single ranking of communication models positioned navigation as the top model, suggesting that it may more faithfully recapitulate underlying neural signaling patterns. We conclude that network communication models augment the functional and behavioral predictive utility of the human structural connectome and contribute to narrowing the gap between brain structure and function.
TGF-beta/Activin ligand Myoglianin couples muscle growth to the initiation of metamorphosis
Authors: He Lorrie L. , Shin Sara Hyun Joo , Wang Zhou , Yuan Isabelle , Weschler Ruthie , Chiou Allie , Koyama Takashi , Nijhout H. Frederik , Suzuki Yuichiro
Published: April 2020

Although the mechanisms that control growth are now well understood, the mechanism by which animals assess their body size remains one of the great puzzles in biology. The final larval instar of holometabolous insects, after which growth stops and metamorphosis begins, is specified by a threshold size. We investigated the mechanism of threshold size assessment in the tobacco hornworm,Manduca sexta. The threshold size was found to change depending on the amount of exposure to poor nutrient conditions whereas hypoxia treatment consistently led to a lower threshold size. Under these various conditions, the mass of the muscles plus integuments was correlated with the threshold size. Furthermore, the expression ofmyoglianin(myo) increased at the threshold size in bothM. sextaandTribolium castaneum. Knockdown ofmyoinT. castaneumled to larvae that underwent supernumerary larval molts and stayed in the larval stage permanently even after passing the threshold size. We propose that increasing levels of Myo produced by the growing tissues allow larvae to assess their body size and trigger metamorphosis at the threshold size.
A midbrain dynorphin circuit promotes threat generalization
Authors: Fellinger Lizz , Jo Yong S. , Hunker Avery C. , Soden Marta E. , Zweifel Larry S.
Published: April 2020

Discrimination between predictive and non-predictive threat stimuli decrease as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identified several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted ‘U’ relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.
A meta-learning approach for genomic survival analysis
Authors: Qiu Yeping Lina , Zheng Hong , Devos Arnout , Gevaert Olivier
Published: April 2020

RNA sequencing has emerged as a promising approach in cancer prognosis as sequencing data becomes more easily and affordably accessible. However, it remains challenging to build good predictive models especially when the sample size is limited and the number of features is high, which is a common situation in biomedical settings. To address these limitations, we propose a meta-learning framework based on neural networks for survival analysis and evaluate it in a genomic cancer research setting. We demonstrate that, compared to regular transfer-learning, meta-learning is a significantly more effective paradigm to leverage high-dimensional data that is relevant but not directly related to the problem of interest. Specifically, meta-learning explicitly constructs a model, from abundant data of relevant tasks, to learn a new task with few samples effectively. For the application of predicting cancer survival outcome, we also show that the meta-learning framework with a few samples is able to achieve competitive performance with learning from scratch with a significantly larger number of samples. Finally, we demonstrate that the meta-learning model implicitly prioritizes genes based on their contribution to survival prediction and allows us to identify important pathways in cancer.
Detecting shared independent selection
Authors: Harris Nathan S. , Rogers Alan R.
Published: April 2020

Signals of selection are not often shared between populations. When a mutual signal is detected, it is often not known if selection occurred before or after populations split. Here we develop a method to detect genomic regions at which selection has favored different haplotypes in two populations. This method is verified through simulations and tested on small regions of the genome. This method was then expanded to scan the phase 3 genomes of the 1000 Genomes Project populations for regions in which the evidence for independent selection is strongest. We identify several genes which likely underwent selection independently in different populations.
TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes
Authors: Zang Ruochen , Castro Maria F.G. , McCune Broc T. , Zeng Qiru , Rothlauf Paul W. , Sonnek Naomi M. , Liu Zhuoming , Brulois Kevin F. , Wang Xin , Greenberg Harry B. , Diamond Michael S. , Ciorba Matthew A. , Whelan Sean P.J. , Ding Siyuan
Published: April 2020

Both gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA have been frequently observed in COVID-19 patients. However, whether SARS-CoV-2 replicate in the human intestine and its clinical relevance to potential fecal-oral transmission remain unclear. Here, we demonstrate productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. In addition to TMPRSS2, another mucosa-specific serine protease, TMPRSS4, also enhanced SARS-CoV-2 spike fusogenic activity and mediated viral entry into host cells. However, newly synthesized viruses released into the intestinal lumen were rapidly inactivated by human colonic fluids and no infectious virus was recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.
Four Families of Folate-independent Methionine Synthases
Authors: Price Morgan N. , Deutschbauer Adam M. , Arkin Adam P.
Published: April 2020

Although most organisms synthesize methionine from homocysteine and methyl folates, some have “core” methionine synthases that lack folate-binding domains and use other methyl donors.In vitro, the characterized core synthases use methylcobalamin as a methyl donor, butin vivo, they probably rely on corrinoid (vitamin B12-binding) proteins. We identified four families of core methionine synthases that are distantly related to each other (under 30% pairwise amino acid identity). From the characterized enzymes, we identified the families MesA, which is found in methanogens, and MesB, which is found in anaerobic bacteria and archaea with the Wood-Ljungdahl pathway. A third uncharacterized family, MesC, is found in anaerobic archaea that have the Wood-Ljungdahl pathway and lack known forms of methionine synthase. We predict that most members of the MesB and MesC families accept methyl groups from the iron-sulfur corrinoid protein of that pathway. The fourth family, MesD, is found only in aerobic bacteria. Using transposon mutants and complementation, we show that MesD does not require 5-methyltetrahydrofolate or cobalamin. Instead, MesD requires an uncharacterized protein family (DUF1852) and oxygen for activity.
Aerial High-Throughput Phenotyping Enabling Indirect Selection for Grain Yield at the Early-generation Seed-limited Stages in Breeding Programs
Authors: Krause Margaret R. , Mondal Suchismita , Crossa José , Singh Ravi P. , Pinto Francisco , Haghighattalab Atena , Shrestha Sandesh , Rutkoski Jessica , Gore Michael A. , Sorrells Mark E. , Poland Jesse
Published: April 2020

Breeding programs for wheat and many other crops require one or more generations of seed increase before replicated yield trials can be sown. Extensive phenotyping at this stage of the breeding cycle is challenging due to the small plot size and large number of lines under evaluation. Therefore, breeders typically rely on visual selection of small, unreplicated seed increase plots for the promotion of breeding lines to replicated yield trials. With the development of aerial high-throughput phenotyping technologies, breeders now have the ability to rapidly phenotype thousands of breeding lines for traits that may be useful for indirect selection of grain yield. We evaluated early generation material in the irrigated bread wheat (Triticum aestivumL.) breeding program at the International Maize and Wheat Improvement Center to determine if aerial measurements of vegetation indices assessed on small, unreplicated plots were predictive of grain yield. To test this approach, two sets of 1,008 breeding lines were sown both as replicated yield trials and as small, unreplicated plots during two breeding cycles. Vegetation indices collected with an unmanned aerial vehicle in the small plots were observed to be heritable and moderately correlated with grain yield assessed in replicated yield trials. Furthermore, vegetation indices were more predictive of grain yield than univariate genomic selection, while multi-trait genomic selection approaches that combined genomic information with the aerial phenotypes were found to have the highest predictive abilities overall. A related experiment showed that selection approaches for grain yield based on vegetation indices could be more effective than visual selection; however, selection on the vegetation indices alone would have also driven a directional response in phenology due to confounding between those traits. A restricted selection index was proposed for improving grain yield without affecting the distribution of phenology in the breeding population. The results of these experiments provide a promising outlook for the use of aerial high-throughput phenotyping traits to improve selection at the early-generation seed-limited stage of wheat breeding programs.
The genomic variation landscape of globally-circulating clades of SARS-CoV-2 defines a genetic barcoding scheme
Authors: Guan Qingtian , Sadykov Mukhtar , Nugmanova Raushan , Carr Michael J. , Arold Stefan T. , Pain Arnab
Published: April 2020

We describe fifteen major mutation events from 2,058 high-quality SARS-CoV-2 genomes deposited up to March 31st, 2020. These events define five major clades (G, I, S, D and V) of globally-circulating viral populations, representing 85.7% of all sequenced cases, which we can identify using a 10 nucleotide genetic classifier or barcode. We applied this barcode to 4,000 additional genomes deposited between March 31stand April 15thand classified successfully 95.6% of the clades demonstrating the utility of this approach. An analysis of amino acid variation in SARS-CoV-2 ORFs provided evidence of substitution events in the viral proteins involved in both host-entry and genome replication. The systematic monitoring of dynamic changes in the SARS-CoV-2 genomes of circulating virus populations over time can guide therapeutic and prophylactic strategies to manage and contain the virus and, also, with available efficacious antivirals and vaccines, aid in the monitoring of circulating genetic diversity as we proceed towards elimination of the agent. The barcode will add the necessary genetic resolution to facilitate tracking and monitoring of infection clusters to distinguish imported and indigenous cases and thereby aid public health measures seeking to interrupt transmission chains without the requirement for real-time complete genomes sequencing.
Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer
Authors: Tello-Lafoz Maria , Srpan Katja , Hu Jing , Romin Yevgeniy , Calò Annalisa , Hsu Katharine C. , Massagué Joan , Huse Morgan , Er Ekrem Emrah
Published: April 2020

Immune cells identify cancer cells by recognizing characteristic biochemical features indicative of oncogenic transformation. Cancer cells have characteristic mechanical features, as well, but whether these biophysical properties also contribute to destruction by the immune system is not known. In the present study, we found that enhanced expression of myocardin related transcription factors (MRTFs), which promote migration and metastatic invasion, paradoxically compromised lung colonization by melanoma and breast carcinoma cells in an immune-mediated manner. Cancer cells with increased MRTF signaling were also more sensitive to immune checkpoint blockade therapy in mice and humans. The basis for this vulnerability was not biochemical, but biophysical. MRTF expression strengthened the actin cytoskeleton, increasing the rigidity of cancer cells and thereby making them more vulnerable to cytotoxic T lymphocytes and natural killer cells. These results reveal a mechanical dimension of immunosurveillance, which we call mechanosurveillance, that is particularly relevant to the targeting of metastatic disease.
Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis
Authors: Romero-Morales Alejandra I. , Robertson Gabriella L. , Rastogi Anuj , Rasmussen Megan L. , Temuri Hoor , McElroy Gregory Scott , Chakrabarty Ram Prosad , Hsu Lawrence , Almonacid Paula M. , Millis Bryan A. , Chandel Navdeep S. , Cartailler Jean-Philippe , Gama Vivian
Published: April 2020

Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions, caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated iPSCs from three patient-derived LS fibroblast lines and identified, by whole-exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS-derived iPSC lines were viable and generally capable of differentiating into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS-derived cerebral organoids showed defects in neural epithelial bud generation, size, and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural progenitor cells with abnormal mitochondrial morphology characterized by fragmentation and disorganization and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used as LS model systems.
Structural basis for active-site probes targetingStaphylococcus aureusserine hydrolase virulence factors
Authors: Fellner Matthias , Lentz Christian S. , Jamieson Sam A. , Brewster Jodi L. , Chen Linhai , Bogyo Matthew , Mace Peter D.
Published: April 2020

Staphylococcus aureusis a major cause of infection in the community and in hospitals. Serine hydrolases play key roles in bacterial homeostasis, in particular biofilms. Activity-based profiling has previously identified a family of serine hydrolases, designated fluorophosphonate-binding hydrolases (Fphs), which contribute to virulence ofS. aureusin the biofilm niche. Here we report structures of the putative tributyrin esterase FphF, alone and covalently bound by a substrate analog, and small molecule inhibitors that occupy the hydrophobic substrate-binding pocket. We show that FphF has promiscuous esterase activity. Building from this, we extended our analysis to the wider Fph protein family using homology modeling and docking tools. We predict that other Fph enzymes, including FphB which was linked directly to virulence, may be more specific than FphF. This study provides insight into Fph function and a template for designing new imaging agents, diagnostic probes, and inhibitors to treatS. aureusinfections.
Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence
Authors: Dahl H.C. , Kanchwala M. , Thomas-Jardin S.E. , Sandhu A. , Kanumuri P. , Nawas A.F. , Xing C. , Lin C. , Frigo D.E. , Delk N.A.
Published: April 2020

Chronic inflammation promotes prostate cancer (PCa) initiation and progression. We previously reported that acute intereluekin-1 (IL-1) exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR- independent PCa cells. We generated isogenic sublines from LNCaP cells chronically exposed to IL-1α or IL-1β. Cells were treated with IL-1α, IL-1β, TNFα or HS-5 bone marrow stromal cells conditioned medium to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation,ARsiRNA silencing and enzalutamide treatment. Finally, RNA sequencing was performed for the IL-1 sublines. MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation- induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA- mediated loss ofAR, serum deprivation and enzalutamide. Differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutivePSArepression and basally highKLK2andNKX3.1mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.
Laboratory sprayer for testing of microbial biocontrol agents: design and calibration
Authors: Erdos Z. , Halswell P. , Matthews A. , Raymond B.
Published: April 2020

The lack of commercially available low-cost laboratory spraying equipment for testing microbial control agents can hinder advancement in the field of biocontrol. This study presents an inexpensive, portable sprayer that is calibrated utilizing laboratory consumables. The computer aided design files are made available so that it is freely modifiable and can be used for machine routing or 3D printing. Bioassay data was obtained by sprayingMyzus persicaewith spores of entomopathogenic fungi. Observed variation in droplet deposition within tested pressure and volume settings, and spore deposition within sprayed concentrations were low. Bioassay results show reproducible mortality for the tested doses.
STAT5 regulation of sex-dependent hepatic CpG methylation at distal regulatory elements mapping to sex-biased genes
Authors: Hao Pengying , Waxman David J.
Published: April 2020

Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver, however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were down regulated in direct association with the loss of STAT5 binding; many female-biased genes, which show low STAT5 binding, were de-repressed, indicating an indirect mechanism for repression by STAT5. Extensive changes in CpG-methylation were seen in STAT5-deficient liver, where sex differences in DNA methylation were abolished at 88% of ~1,500 differentially-methylated regions, largely due to an increase in methylation at the hypomethylated sites. STAT5-dependent CpG-hypomethylation was rarely found at proximal promoters of STAT5-dependent genes. Rather, STAT5 primarily regulated the methylation of distal enhancers, where STAT5 deficiency induced widespread hypermethylation at genomic regions enriched for accessible chromatin, enhancer histone marks (H3K4me1, H3K27ac), STAT5 binding, and DNA motifs for STAT5 and other transcription factors implicated in liver sex differences. In conclusion, the sex-dependent binding of STAT5 to liver chromatin is closely linked to sex-dependent demethylation of distal regulatory elements mapping to STAT5-dependent genes important for liver sex bias.
Megaevolutionary dynamics in reptiles and the role of adaptive radiations in evolutionary innovation
Authors: Simões Tiago R. , Vernygora Oksana , Caldwell Michael W. , Pierce Stephanie E.
Published: April 2020

Adaptive radiations are long believed to be responsible for the origin of phenotypic diversity and new body plans among higher clades in the fossil record. However, few studies have assessed rates of phenotypic evolution and disparity across broad scales of time to understand the evolutionary dynamics behind the origin of major clades, or how they relate to rates of molecular evolution. Here, we provide a total evidence approach to this problem using the largest available data set on diapsid reptiles. We find a strong decoupling between phenotypic and molecular rates of evolution, with many periods of accelerated phenotypic evolution or expansion of phenotypic disparity at the origin of major reptile clades and body plans that do not correspond to periods of adaptive radiation. We find heterogeneous rates of evolution during the acquisition of similarly adapted functional types, and that the origin of snakes is marked by exceptionally high evolutionary rates.
Seasonal weight changes in laboratory ferrets
Authors: Jones Eleanor J. , Poole Katarina , Sollini Joseph , Town Stephen M. , Bizley Jennifer K.
Published: April 2020

Ferrets (Mustela putorius furo) are a valuable animal model used in biomedical research. Ferrets undergo significant variation in body weight seasonally, affected by photoperiod, and these variations make it difficult to use weight as an indicator of health status. To overcome this requires a better understanding of these seasonal weight changes. We provide a normative weight data set for the female ferret accounting for seasonal changes, and also investigate the effect of fluid regulation on weight change. Female ferrets (n=39) underwent behavioural testing from May 2017 to August 2019 and were weighed daily while housed in an animal care facility with controlled light exposure. In the winter (October to March), animals experienced 10 hours of light and 14 hours of dark, while in summer (March to October), this contingency was reversed. Individual animals varied in their body weight from approximately 700 to 1200 g. However, weights fluctuated with light cycle, with animals losing weight in summer, and gaining weight in winter such that they fluctuated between approximately 80% and 120% of their long term average weight. Ferrets were weighed as part of their health assessment while experiencing water regulation for behavioural training. Water regulation superimposed additional weight changes on these seasonal fluctuations, with weight loss during the 5 day water regulation period being greater in summer than winter. These data establish a normative benchmark for seasonal weight variation in female ferrets that can be incorporated into the health assessment of an animal’s condition.
Decreased torsinA or LINC Complex Function Rescues a Laminopathy inCaenorhabditis elegans
Authors: Huelgas-Morales Gabriela , Sanders Mark , Mekonnen Gemechu , Tsukamoto Tatsuya , Greenstein David
Published: April 2020

The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex spanning the nuclear envelope. In turn, the AAA+ ATPase torsinA regulates force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia. We report that decreasing the function of theC. eleganstorsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog,lmn-1. Loss of OOC-5 activity prevents nuclear collapse inlmn-1mutants by disrupting the function of the LINC complex. These results suggest that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina.

One Sentence Summary

Inhibiting LINC complex activity prevents a progeric syndrome inC. elegans.
PlanktonScope: Affordable modular imaging platform for citizen oceanography
Authors: Pollina Thibaut , Larson Adam G. , Lombard Fabien , Li Hongquan , Colin Sebastien , de Vargas Colomban , Prakash Manu
Published: April 2020

The planktonic communities within our oceans represent one of the most diverse and understudied ecosystems on the planet. A major hurdle in describing these systems is the sheer scale of the oceans along with logistical and economic constraints associated with their sampling. This is due to the limited amount of scientifically equipped fleets and affordable equipment. Here we demonstrate a modular approach for building a versatile, re-configurable imaging platform that can be adapted to a number of field applications, specifically focusing on oceanography. By using a modular hardware/software approach for building microscopes, we demonstrate high-throughput imaging of lab and field samples while enabling rapid device reconfiguration in order to match diverse applications and the evolving needs of the sampler. The presented versions of PlanktonScope are capable of autonomously imaging 1.7 ml per minute with a 1.5 µm resolution, and are built with under $400 in parts. This low cost enables new applications in laboratory settings such as the continuous imaging of suspension cultures, and in-field settings with the ability to scale up for long-term deployment on an international fleet of sailing boats enabling citizens based oceanographic research