bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the Trajectory of Any COVID19 Epidemic From the Best Straight Line
Authors: Levitt Michael , Scaiewicz Andrea , Zonta Francesco
Published: June 2020

A pipeline involving data acquisition, curation, carefully chosen graphs and mathematical models, allows analysis of COVID-19 outbreaks at 3,546 locations world-wide (all countries plus smaller administrative divisions with data available). Comparison of locations with over 50 deaths shows all outbreaks have a common feature: H(t) defined as loge(X(t)/X(t-1)) decreases linearly on a log scale, where X(t) is the total number of Cases or Deaths on day, t (we use ln for loge). The downward slopes vary by about a factor of three with time constants (1/slope) of between 1 and 3 weeks; this suggests it may be possible to predict when an outbreak will end. Is it possible to go beyond this and perform early prediction of the outcome in terms of the eventual plateau number of total confirmed cases or deaths?

We test this hypothesis by showing that the trajectory of cases or deaths in any outbreak can be converted into a straight line. Specifically Y(t) ≡ −ln(ln(N / X (t)), is a straight line for the correct plateau value N, which is determined by a new method, Best-Line Fitting (BLF). BLF involves a straight-line facilitation extrapolation needed for prediction; it is blindingly fast and amenable to optimization. We find that in some locations that entire trajectory can be predicted early, whereas others take longer to follow this simple functional form. Fortunately, BLF distinguishes predictions that are likely to be correct in that they show a stable plateau of total cases or death (N value). We apply BLF to locations that seem close to a stable predicted N value and then forecast the outcome at some locations that are still growing wildly. Our accompanying web-site will be updated frequently and provide all graphs and data described here.
Forecasting COVID-19 Dynamics and Endpoint in Bangladesh: A Data-driven Approach
Authors: Hridoy Al-Ekram Elahee , Naim Mohammad , Emon Nazim Uddin , Tipo Imrul Hasan , Alam Safayet , Al Mamun Abdullah , Islam Mohammad Safiqul
Published: June 2020

On December 31, 2019, the World Health Organization (WHO) was informed that atypical pneumonia-like cases have emerged in Wuhan City, Hubei province, China. WHO identified it as a novel coronavirus and declared a global pandemic on March 11th, 2020. At the time of writing this, the COVID-19 claimed more than 440 thousand lives worldwide and led to the global economy and social life into an abyss edge in the living memory. As of now, the confirmed cases in Bangladesh have surpassed 100 thousand and more than 1343 deaths putting startling concern on the policymakers and health professionals; thus, prediction models are necessary to forecast a possible number of cases in the future. To shed light on it, in this paper, we presented data-driven estimation methods, the Long Short-Term Memory (LSTM) networks, and Logistic Curve methods to predict the possible number of COVID-19 cases in Bangladesh for the upcoming months. The results using Logistic Curve suggests that Bangladesh has passed the inflection point on around 28-30 May 2020, a plausible end date to be on the 2nd of January 2021 and it is expected that the total number of infected people to be between 187 thousand to 193 thousand with the assumption that stringent policies are in place. The logistic curve also suggested that Bangladesh would reach peak COVID-19 cases at the end of August with more than 185 thousand total confirmed cases, and around 6000 thousand daily new cases may observe. Our findings recommend that the containment strategies should immediately implement to reduce transmission and epidemic rate of COVID-19 in upcoming days.

Highlights

According to the Logistic curve fitting analysis, the inflection point of the COVID-19 pandemic has recently passed, which was approximately between May 28, 2020, to May 30, 2020.

It is estimated that the total number of confirmed cases will be around 187-193 thousand at the end of the epidemic. We expect that the actual number will most likely to in between these two values, under the assumption that the current transmission is stable and improved stringent policies will be in place to contain the spread of COVID-19.

The estimated total death toll will be around 3600-4000 at the end of the epidemic.

The epidemic of COVID-19 in Bangladesh will be mostly under control by the 2nd of January 2021 if stringent measures are taken immediately.
Cost effectiveness of interventions for Post-Traumatic Stress Disorders following major incidents including terrorism and pandemics
Authors: Hogan Nicole , Knapp Martin , McDaid David , Davies Mark , Brewin Chris R.
Published: June 2020

Background

Post-traumatic stress disorder (PTSD) is commonly experienced in the aftermath of major incidents such as terrorism and pandemics. Well-established principles of response include effective and scalable treatment for individuals affected by PTSD. In England, such responses have combined proactive outreach, screening, and evidence-based interventions (a “screen-and-treat” approach), but little is known about the cost-effectiveness of this approach.

Methods

A decision modelling analysis was undertaken to estimate the costs per quality adjusted life year (QALY) gained from a screen-and-treat approach compared to treatment-as-usual. Model input variables were drawn from relevant empirical studies in the context of terrorism and the unit costs of health and social care in England. The model was run over a five-year time horizon for a hypothetical cohort of 1,000 exposed adults from the perspective of the National Health Service and Personal Social Services in England.

Results

The incremental cost per QALY gained was £8,297. This would be considered cost-effective 95% of the time at a willingness-to-pay threshold of £20,000 per QALY gained, the threshold associated with NICE. Sensitivity analysis confirmed this result was robust.

Conclusions

A screen-and-treat approach for identifying and treating PTSD in adults following major incidents appears cost-effective in England compared to treatment-as-usual through conventional primary care routes. This finding was in the context of terrorism but can be translatable into other major-incident related scenarios including the current COVID-19 pandemic in lieu of data on the impact of this pandemic.

Competing interest statement

The authors have declared no competing interest.

Funding statement

No additional funding was provided for this study

Author Declarations

All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.

Yes

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes
Analyses and Forecast for COVID-19 epidemic in India
Authors: Banerjee Rudra , Bhattacharjee Srijit , Varadwaj Pritish Kumar
Published: June 2020

COVID-19 is a highly infectious disease that is causing havoc to the entire world due to the newly discovered coronavirus SARS-CoV-2. In this study, the dynamics of COVID-19 for India and a few selected states with different demographic structures have been analyzed using a SEIRD epidemiological model. A systematic estimation of the basic reproductive ratio R0 is made for India and for each of the selected states. The study has analysed and predicted the dynamics of the temporal progression of the disease in Indian and the selected eight states: Andhra Pradesh, Chhattisgarh, Delhi, Gujarat, Madhya Pradesh, Maharashtra, Tamil Nadu, and Uttar Pradesh. For India, the most optimistic scenario with respect to duration of the epidemic shows, the peak of infection will appear before mid September with the estimated R0 = 1.917, from the SEIRD model. Further, we show, a Gaussian fit of the daily incidences also indicates the peak will appear around middle of August this year. Our analyses suggest, the earliest dates when the epidemic will start to decline in most states are between Jun-August. For India, the number of infected people at the time of peak will be around 1.6 million including asymptomatic people. If the community transmission is prohibited, then the epidemic will infect not more than 3.1 million people in India. We also compared India’s position in containing the disease with two countries with higher and lower number of infections than India and show the early imposition of lockdown has reduced the number of infected cases significantly.
Adjusting confirmed COVID-19 case counts for testing volume
Authors: Favero Nathan
Published: June 2020

When assessing the relative prevalence of the novel coronavirus (COVID-19), observers often point to the number of COVID-19 cases that have been confirmed through viral testing. However, comparisons based on confirmed case counts alone can be misleading since a higher case count may reflect either a higher disease prevalence or a better rate of disease detection. Using weekly records of viral test results for each state in the US, I demonstrate how confirmed case counts can be adjusted based on the percentage of COVID-19 tests that come back positive. A regression analysis indicates that case counts track better with future hospitalizations and deaths when employing this simple adjustment for testing coverage. Viral testing results can be used as a leading indicator of COVID-19 prevalence, but data reporting standards should be improved, and care should be taken to account for testing coverage when comparing confirmed case counts.
Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer
Authors: Gardner Ivy H. , Siddharthan Ragavan , Watson Katherine , Dewey Elizabeth , Ruhl Rebecca , Guan Xiangnan , Xia Zheng , Tsikitis Liana V. , Anand Sudarshan
Published: June 2020

Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes.
Social media and smartphone app use predicts maintenance of physical activity during Covid-19 enforced isolation in psychiatric outpatients
Authors: Norbury Agnes , Liu Shelley H , Campaña-Montes Juan José , Romero-Medrano Lorena , Barrigon Maria L. , Smith Emma ,   MEmind Study Group, Artes Antonio , Baca-Garcia Enrique , Perez-Rodriguez M. Mercedes
Published: June 2020

Public health professionals have raised concerns that the social and physical distancing measures implemented in response to the Covid-19 pandemic may negatively impact health in other areas, via both decreased physical activity and increased social isolation. Here, we investigated whether increased engagement with digital social tools may help mitigate effects of enforced isolation on physical activity and mood, in a naturalistic study of at-risk individuals. Passively sensed smartphone app use and actigraphy data, collected from a sample of psychiatric outpatients both before and during imposition of strict lockdown conditions (N=163), were analysed using Gaussian graphical models: a form of network analysis which gives insight into the predictive relationships between measures across timepoints. Within-individuals, we found evidence of a positive predictive path between digital social engagement, general smartphone use, and physical activity – selectively under lockdown conditions. Further, we observed a positive relationship between social media use and total daily steps across individuals during (but not prior to) lockdown. We interpret these findings in terms of individuals using these digital tools to harness online social support structures, which may help guard against negative effects of in-person social deprivation and other pandemic-related stress. Monitoring of these measures is low burden and unintrusive and therefore, given appropriate consent, could potentially help identify individuals who are failing to engage this mechanism, providing a route to early intervention in this and other vulnerable populations.
Association study of DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 with Parkinson’s disease
Authors: Saini Prabhjyot , Rudakou Uladzislau , Yu Eric , Ruskey Jennifer A. , Asayesh Farnaz , Laurent Sandra B. , Spiegelman Dan , Fahn Stanley , Waters Cheryl , Monchi Oury , Dauvilliers Yves , Dupré Nicolas , Greenbaum Lior , Hassin-Baer Sharon , Espay Alberto J. , Rouleau Guy A. , Alcalay Roy N. , Fon Edward A. , Postuma Ronald B. , Gan-Or Ziv
Published: June 2020

Rare mutations in genes originally discovered in multi-generational families have been associated with increased risk of Parkinson’s Disease (PD). The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 loci have been poorly studied or produced conflicting results across cohorts. However, they are still being often referred to as “PD-genes” and used in different models. To further elucidate the role of these five genes in PD, we fully sequenced them using molecular inversion probes in 2,408 PD patients and 3,444 controls from 3 different cohorts. A total of 788 rare variants were identified across the five genes and three cohorts. Burden analyses and optimized sequence Kernel association tests revealed no significant association between any of the genes and PD after correction for multiple comparisons. Our results do not support an association of the five tested genes with PD. Combined with previous studies, it is unlikely that any of these genes plays an important role in PD. Their designation as “PARK” genes should be reconsidered.
Memory-Dependent Model for the Dynamics of COVID-19 Pandemic
Authors: Furati K.M. , Sarumi I.O. , Khaliq A.Q.M.
Published: June 2020

COVID-19 pandemic has impacted people all across the world. As a result, there has been a collective effort to monitor, predict, and control the spread of this disease. Among this effort is the development of mathematical models that could capture accurately the available data and simulate closely the futuristic scenarios. In this paper, a fractional-order memory-dependent model for simulating the spread of COVID-19 is proposed. In this model, the impact of governmental action and public perception are incorporated as part of the time-varying transmission rate. The model simulation is performed using the two-step generalized exponential time-differencing method and tested for data from Wuhan, China. The mean-square errors demonstrate the merit of the fractional-order model and provide a good estimate of the optimal order.
Predictors of postoperative biochemical remission in acromegaly
Authors: Yao Shun , Chen Wen-Li , Tavakol Sherwin , Akter Farhana , Catalino Michael P. , luo Jie , Guo Xiao-Peng , Zeng Ai-Liang , Zekelman Leo , Mao Zhi-Gang , Zhu Yong-Hong , Wu Qing-Zhi , Laws Edward R , Bi Wenya Linda , Wang Hai-Jun
Published: June 2020

OBJECTIVE

Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity; therefore, large studies are invaluable for understanding the disease burden. Despite China’s vast population size, studies on acromegaly remain sparse. In this report, we aimed to investigate clinical characteristics and predictors of biochemical remission after surgery for acromegaly.

METHODS

A retrospective nationwide study was conducted using patient-reported data from the China Acromegaly Patient Association (CAPA) from 1998 to 2018. Univariate analyses were performed using Wilcoxon rank-sum tests, two-sample t-tests, and chi-squared tests. Using the purposeful selection method, multivariate logistic regression analysis was employed to determine independent predictors of biochemical remission at 3 months in patients after surgery.

RESULTS

Of the 575 cases (mean age: 37.3 years; 59% female), macroadenomas and invasive tumors (Knosp score 3-4) were 87% and 61%, respectively. Ninety-five percent of patients were treated first with surgery (5.1% transcranial and 94.9% endonasal) and 38.3% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 μg/L [odds ratio (OR)=0.61; 95% confidence interval (CI), 0.39-0.96; p=0.031], preoperative GH levels >28 μg/L (OR=0.56; 95% CI, 0.35-0.90; p=0.016), macroadenoma (OR=0.57; 95% CI, 0.33-0.97; p=0.041), giant adenomas (OR=0.17; 95% CI, 0.06-0.44; p=0.0005), Knosp score 3-4 (OR=0.39; 95% CI, 0.25-0.59; p<0.0001), and preoperative medication usage (OR=2.16; 95% CI, 1.38-3.39; p=0.0008).

CONCLUSIONS

In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.
A Streamlined CyTOF Workflow To Facilitate Standardized Multi-Site Immune Profiling of COVID-19 Patients
Authors: Geanon Daniel , Lee Brian , Kelly Geoffrey , Handler Diana , Upadhyaya Bhaskar , Leech John , Herbinet Manon , Valle Diane Del , Gnjatic Sacha , Kim-Schulze Seunghee , Merad Miriam , Rahman Adeeb H.
Published: June 2020

Mass cytometry (CyTOF) represents one of the most powerful tools in immune phenotyping, allowing high throughput quantification of over 40 single parameters at single-cell resolution. However, wide deployment of CyTOF-based immune phenotyping studies are limited by complex experimental workflows and the need for specialized CyTOF equipment and technical expertise. Furthermore, differences in cell isolation and enrichment protocols, antibody reagent preparation, sample staining and data acquisition protocols can all introduce technical variation that can potentially confound integrative analyses of large data-sets of samples processed across multiple labs.

Here, we describe the validation of a streamlined whole blood CyTOF workflow that addresses many of these challenges and facilitates wider adoption of CyTOF immune monitoring across sites with limited technical expertise or sample-processing resources or equipment. Our workflow utilizes commercially available reagents including the Fluidigm MaxPar Direct Immune Profiling Assay, a dry tube 30-marker immunophenotyping panel, and SmartTube Proteomic Stabilizer, which allows for simple and reliable fixation and cryopreservation of whole blood samples. We validate a workflow that allows for streamlined staining of whole blood samples with minimal processing requirements or expertise at the site of sample collection, followed by shipment to a central CyTOF core facility for batched downstream processing and data acquisition. We further demonstrate the application of this workflow to characterize immune responses in a cohort of hospitalized COVID-19 patients, highlighting key disease-associated changes in immune cell frequency and phenotype.
Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory
Authors: Gangishetti Umesh , Ramirez-Perez Sergio , Jones Kyle , Arif Abul , Drissi Hicham , Bhattaram Pallavi
Published: June 2020

Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.
In silico prediction of structure and function for a large family of transmembrane proteins that includes human Tmem41b
Authors: Mesdaghi Shahram , Murphy David L. , Rodríguez Filomeno Sánchez , Burgos-Mármol J. Javier , Rigden Daniel J.
Published: June 2020

Recent strides in computational structural biology have opened up an opportunity to understand previously mysterious uncharacterised proteins. The under-representation of transmembrane proteins in the Protein Data Bank highlights the need to apply new and advanced bioinformatics methods to shed light on their structure and function. This study focuses on such a family; transmembrane proteins containing the Pfam domain PF09335 (‘SNARE_ASSOC’/‘VTT ‘/‘Tvp38’). One prominent member, Tmem41b, has been shown to be involved in early stages of autophagosome formation and is vital in mouse embryonic development. Here we use evolutionary covariance-derived information not only to construct and validateab initiomodels but also to make domain boundary predictions and infer local structural features. The results from the structural bioinformatics analysis of Tmem41b and its homologues show that they contain a tandem repeat that is clearly visible in evolutionary covariance data but much less so by sequence analysis. Furthermore, cross-referencing of other prediction data with the covariance analysis shows that the internal repeat features 2-fold rotational symmetry.Ab initiomodelling of Tmem41b reinforces these structural predictions. Local structural features predicted to be present in Tmem41b are also present in Cl−/H+antiporters. These results together strongly point to Tmem41b and its homologues as being transporters for an as-yet uncharacterised substrate and possibly using H+antiporter activity as its mechanism for transport.
A Role for Maternal Factors in Suppressing Cytoplasmic Incompatibility
Authors: Momtaz AJM Zehadee , Ahumada Sabagh Abraham D. , Amortegui Julian Gonzalez , Salazar Samuel A. , Finessi Andrea , Hernandez Jethel , Christensen Steen , Serbus Laura R.
Published: June 2020

Wolbachiaare maternally transmitted bacterial endosymbionts, carried by approximately half of all insect species.Wolbachiaprevalence in nature stems from manipulation of host reproduction to favor the success of infected females. The best known reproductive modification induced byWolbachiais referred to as sperm-egg Cytoplasmic Incompatibility (CI). In CI, the sperm ofWolbachia-infected males cause embryonic lethality, attributed to paternal chromatin segregation defects during early mitotic divisions. Remarkably, the embryos ofWolbachia-infected females “rescue” CI lethality, yielding egg hatch rates equivalent to uninfected female crosses. Several models have been discussed as the basis for Rescue, but none have been demonstrated in robust CI models, which are genetically intractable. As such, the extent of host involvement in Rescue remains untested. In this study, we used a chemical feeding approach to assess maternal contributions to CI suppression inDrosophila simulans. We found that uninfected females exhibited significantly higher CI egg hatch rates in response to seven chemical treatments that affect DNA integrity, cell cycle control, and protein turnover. Three of these treatments suppressed CI induced by endogenouswRiWolbachia, as well as an ectopicwMelWolbachiainfection. When framed in terms of existing literature, the results implicate DNA integrity as a dynamic aspect of CI suppression for differentWolbachiastrains. The framework presented here, applied to diverse CI models, will further enrich our understanding of host reproductive manipulation by insect endosymbionts.
The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases
Authors: Coleman James L. J. , Ngo Tony , Smythe Rhyll E. , Cleave Andrew J. , Jones Nicole M. , Graham Robert M. , Smith Nicola J.
Published: June 2020

GPR37L1 is an orphan G protein-coupled receptor expressed exclusively in the brain and linked to seizures, neuroprotection and cardiovascular disease. Based upon the observation that fragments of the GPR37L1 N-terminus are found in human cerebrospinal fluid, we hypothesized that GPR37L1 was subject to post-translational modification. Heterologous expression of GPR37L1-eYFP in either HEK293 or U87 glioblastoma cells yielded two cell surface species of approximately equivalent abundance, the larger of which is N-glycosylated at Asn105. The smaller species is produced by matrix metalloprotease/ADAM-mediated proteolysis (shown by the use of pharmacological inhibitors) and has a molecular weight identical to that of a mutant lacking the entire N-terminus, Δ122 GPR37L1. Serial truncation of the N-terminus prevented GPR37L1 expression except when the entire N-terminus was removed, narrowing the predicted site of N-terminal proteolysis to residues 105-122. Using yeast expressing different G protein chimeras, we found that wild type GPR37L1, but not Δ122 GPR37L1, coupled constitutively to Gpa1/Gαs and Gpa1/Gα16 chimeras, in contrast to previous studies. We tested the peptides identified in cerebrospinal fluid as well as their putative newly-generated N-terminal ‘tethered’ counterparts in both wild type and Δ122 GPR37L1 Gpa1/Gαs strains but saw no effect, suggesting that GPR37L1 does not signal in a manner akin to the protease-activated receptor family. We also saw no evidence of receptor activation or regulation by the reported GPR37L1 ligand, prosaptide/TX14A. Finally, the proteolytically processed species predominated bothin vivoandex vivoin organotypic cerebellar slice preparations, suggesting that GPR37L1 is rapidly processed to a signaling-inactive form. Our data indicate that the function of GPR37L1in vivois tightly regulated by metalloprotease-dependent N-terminal cleavage.
Classification of grain amaranths using chromosome-level genome assembly of ramdana,A. hypochondriacus
Authors: Deb Saptarathi , J Suvratha , Ravi Samathmika , Rao K Raksha , Whadgar Saurabh , Hariharan Nivedita , Dixit Shubham , Sunil Meeta , Choudhary Bibha , Stevanato Piergiorgio , Ramireddy Eswarayya , Srinivasan Subhashini
Published: June 2020

In the age of genomics-based crop improvement, a high-quality genome of a local landrace adapted to the local environmental conditions is critically important. Grain amaranths produce highly nutritional grains with a multitude of desirable properties including C4 photosynthesis highly sought-after in other crops. For improving the agronomic traits of grain amaranth and for the transfer of desirable traits to dicot crops, a reference genome of a local landrace is necessary. Towards this end, our lab had initiated sequencing the genome ofAmaranthus (A.) hypochondriacus(A.hyp_K_white) and had reported a draft genome in 2014. We selected this landrace because it is well adapted for cultivation in India during the last century and is currently a candidate for TILLING-based crop improvement. More recently, a high-quality chromosome-level assembly ofA. hypochondriacus(PI558499, Plainsman) was reported. Here, we report a chromosome-level assembly of A.hyp_K_white (AhKP) using low-coverage PacBio reads, contigs from the reported draft genome of A.hyp_K_white, raw HiC data and reference genome of Plainsman. The placement of A.hyp_K_white on the phylogenetic tree of grain amaranths of known accessions clearly suggests that A.hyp_K_white is genetically distal from Plainsman and is most closely related to the accessionPI619259from Nepal (Ramdana). Furthermore, the classification of another accession, Suvarna, adapted to the local environment and selected for yield and other desirable traits, is clearlyA. cruentus. A classification based on hundreds of thousands of SNPs validated taxonomy-based classification for a majority of the accessions providing the opportunity for reclassification of a few.
Folate and Tolazamide: Potential competitive inhibitors of barbiturate by in-silico molecular docking
Authors: Sharp Kumar
Published: June 2020

Barbiturates are the first line drugs for treatment of epilepsy for adults and children in the developing world because of its low cost and proven effectiveness. Due to their adverse effects, no effective management of toxicity and difficulty in determining correct dosage, benzodiazepines are preferred over them. It is also used as a recreational drug, thereby contributing to cases of overdose. My present study was to find the inhibitors of barbiturates by in-silico molecular docking. This approach can highlight only competitive inhibitors as molecules in-silico are rigid and do not produce conformational changes in structure by allosteric binding. 450 FDA-approved drugs were docked to active site of barbiturate of Gleobacter ligand-gated ion channel (GLIC). Drug interactions were visualized, literature search was done to bring out the final results. Tolazamide, an oral anti-diabetic drug and 5-methyltetrahydrofolate, active metabolite of folic acid produced desired results. These results should be used clinically for validation.
Structures, conformations and distributions of SARS-CoV-2 spike protein trimers on intact virions
Authors: Ke Zunlong , Oton Joaquin , Qu Kun , Cortese Mirko , Zila Vojtech , McKeane Lesley , Nakane Takanori , Zivanov Jasenko , Neufeldt Christopher J. , Lu John M. , Peukes Julia , Xiong Xiaoli , Kräusslich Hans-Georg , Scheres Sjors H.W. , Bartenschlager Ralf , Briggs John A.G.
Published: June 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions are surrounded by a lipid bilayer from which spike (S) protein trimers protrude. Heavily glycosylated S trimers bind the ACE2 receptor and mediate entry of virions into target cells. S exhibits extensive conformational flexibility: it modulates the exposure of its receptor binding site and later undergoes complete structural rearrangement to drive fusion of viral and cellular membranes. The structures and conformations of soluble, overexpressed, purified S proteins have been studied in detail using cryo-electron microscopy. The structure and distribution of S on the virion surface, however, has not been characterised. Here we applied cryo-electron microscopy and tomography to image intact SARS-CoV-2 virions, determining the high-resolution structure, conformational flexibility and distributions of S trimers in situ on the virion surface. These results provide a basis for understanding the conformations of S present on the virion, and for studying their interactions with neutralizing antibodies.
First responders shape a prompt and sharp NF-κB–mediated transcriptional response to TNF-α
Authors: Zambrano Samuel , Loffreda Alessia , Carelli Elena , Stefanelli Giacomo , Colombo Federica , Bertrand Edouard , Tacchetti Carlo , Agresti Alessandra , Bianchi Marco E. , Molina Nacho , Mazza Davide
Published: June 2020

NF-κB acts as the master regulator of the transcriptional response to inflammatory signals by translocating into the nucleus upon stimuli, but we lack a single-cell characterization of the resulting transcription dynamics. Here we show that transcription of NF-κB target genes is strongly heterogeneous in individual cells but dynamically coordinated at the population level, since the average nascent transcription is prompt (i.e. occurs almost immediately) and sharp (i.e. increases and decreases rapidly) compared to NF-κB nuclear localization. Using an NF-κB-controlled MS2 reporter we confirm that the population-level transcriptional activity emerges from a strongly heterogeneous response in single cells as compared to NF-κB translocation dynamics, including the presence of a fraction of “first responders”. Mathematical models show that a combination of NF-κB mediated gene activation and a gene activity module including a gene refractory state is enough to produce sharp and prompt transcriptional responses. Our data and models show how the expression of the target genes of a paradigmatic inducible transcription activator upon stimuli can be time-resolved at population level and yet heterogeneous across single cells.
Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma
Authors: Mehboob Riffat , Gilani Syed Amir , Hassan Amber , Tanvir Imrana , Khan Rizwan Ullah , Javaid Shaista , Akram Javed ,   Sadaf, Ahmad Fridoon Jawad , Munoz Miguel
Published: June 2020

To evaluate the expression and Immunolocalization of Substance P (SP)/ Neurokinin-1 Receptor (NK-1R) in Breast Carcinoma (BC) patients and it’s association with routine proliferative markers (ER, PR, HER2/ neu and Ki-67).

Methods

A cross-sectional study was performed on 34 cases of BC. There were 23 cases of group A (Grade III), 8 of group B (Grade II) and only 3 cases of group C (Grade I). Age range comprised of patients from 20-80 years and the mean age of patients was 45.74 years. HE, ER, PR, HER2 and Ki-67 staining was performed as routine biomarkers. Samples were then processed for immunomarkers study of Substance P and NK-1R immunohistochemistry was performed for few cases.

Results

14/23 cases (61%) of group A, 7/8 cases (88%) of group B and 2/3 (67%) cases of group C were SP positive. Overall, strong staining (≥ 10% tumors cells), labeled as “3+”, was observed in 9/14 (64.2%) cases of group A and 1/8 (12.5%) case of group B. Moderate staining labelled as “2+” (in ≥ 10% tumor cells) was observed in 3/14 (21.4%) cases of group A, 4/8 (50%) cases of group B. weak positive staining “1+” was observed in only 2/14 (14.28%) cases of group A, 2/8 (25%) cases of group B and all 2/2 (100%) cases of group C.

Conclusions

SP and NK-1R is overexpressed in breast carcinomas and there is significant association between grade of tumor and their overexpression. It may serve as a novel biomarker for grading of BC. We also suggest that NK-1R antagonists as a potential therapeutic strategy to inhibit and manage BC.

Key Points

Immunohistochemical expression of Substance P and Neurokinin 1 Receptor in breast carcinoma tissue was evaluated

It was strongly expressed in grade III, with maximum intensity

It may be investigated further for its role as prognostic and diagnostic marker

Therapeutic potential of Neurokinin-1 Receptor antagonists must be explored
pixy: Unbiased estimation of nucleotide diversity and divergence in the presence of missing data
Authors: Korunes Katharine L , Samuk Kieran
Published: June 2020

Population genetic analyses often use summary statistics to describe patterns of genetic variation and provide insight into evolutionary processes. Among the most fundamental of these summary statistics areπanddXY, which are used to describe genetic diversity within and between populations, respectively. Here, we address a widespread issue inπanddXYcalculation: systematic bias generated by missing data of various types. Many popular methods for calculatingπanddXYoperate on data encoded in the Variant Call Format (VCF), which condenses genetic data by omitting invariant sites. When calculatingπanddXYusing a VCF, it is often implicitly assumed that missing genotypes (including those at sites not represented in the VCF) are homozygous for the reference allele. Here, we show how this assumption can result in substantial downward bias in estimates ofπanddXYthat is directly proportional to the amount of missing data. We discuss the pervasive nature and importance of this problem in population genetics, and introduce a user-friendly UNIX command line utility,pixy, that solves this problem via an algorithm that generates unbiased estimates ofπanddXYin the face of missing data. We comparepixyto existing methods using both simulated and empirical data, and show thatpixyalone produces unbiased estimates ofπanddXYregardless of the form or amount of missing data. In sum, our software solves a long-standing problem in applied population genetics and highlights the importance of properly accounting for missing data in population genetic analyses.
Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor
Authors: Krämer Andreas , Kurz Christian Georg , Berger Benedict-Tilman , Celik Ibrahim Ethem , Knapp Stefan , Hanke Thomas
Published: June 2020

Casein kinase 2 (CK2) is a constitutively expressed serine/threonine kinase that has a large diversity of cellular substrates. Thus, CK2 has been associated with a plethora of regulatory functions and dysregulation of CK2 has been linked to disease development in particular to cancer. The broad implications in disease pathology makes CK2 an attractive target. To date, the most advanced CK2 inhibitor is silmitasertib, which has been investigated in clinical trials for treatment of various cancers, albeit several off-targets for silmitasertib have been described. To ascertain the role of CK2 inhibition in cancer, other disease and normal physiology the development of a selective CK2 inhibitor would be highly desirable. In this study we explored the pyrazolo[1,5-a]pyrimidine hinge-binding moiety for the development of selective CK2 inhibitors. Optimization of this scaffold, which included macrocyclization, led toIC20(31) a compound that displayed highin vitropotency for CK2 (KD= 12 nM) and exclusive selectivity for CK2. X-ray analysis revealed a canonical type-I binding mode forIC20. However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency and reduced somewhat cellular activity. In summary,IC20represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.

Notes

The authors declare no conflict of interest.

TOC Figure / Graphical Abstract
Contrasting hierarchical and multiple-demand accounts of frontal lobe functional organisation during task-switching
Authors: Daws Richard E. , Soreq Eyal , Li Yuqi , Sandrone Stefano , Hampshire Adam
Published: June 2020

There is an unresolved discrepancy between popular hierarchical and multiple-demand perspectives on the functional organisation of the human frontal lobes. Here, we tested alternative predictions of these perspectives with a novel fMRI switching paradigm. Each trial involved switching attention between stimuli, but at different levels of difficulty and abstraction. As expected, increasing response times were evident when comparing low-level perceptual switching to more abstract dimension, rule and task-switching. However, there was no evidence of an abstraction hierarchy within the prefrontal cortex (PFC). Nor was there recruitment of additional anterior PFC regions under increased switching demand. Instead, switching activated a widespread network of frontoparietal and cerebellar regions. Critically, the activity within PFC sub-regions uniformly increased with behavioural switch costs. We propose that both perspectives have some validity, but neither is complete. Too many studies have reported dissociations within MD for this volume to be functionally uniform, and the recruitment of more anterior regions with increased general difficulty cannot explain those results. Conversely, whilst reproducible evidence for a hierarchical functional organisation has been reported, this cannot be explained in terms of abstraction of representation or reconfigurationper se, because those interpretations generalise poorly to other task contexts.
Modified Vaccinia Ankara Based SARS-CoV-2 Vaccine Expressing Full-Length Spike Induces Strong Neutralizing Antibody Response
Authors: Routhu Nanda Kishore , Gangadhara Sailaja , Cheedarla Narayanaiah , Shiferaw Ayalnesh , Rahman Sheikh Abdul , Sahoo Anusmita , Shi Pei-Yong , Menachery Vineet D. , Floyd Katharine , Fischinger Stephanie , Atyeo Caroline , Alter Galit , Suthar Mehul S. , Amara Rama Rao
Published: June 2020

There is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.
I-KCKT allows dissection-free RNA profiling of adultDrosophilaintestinal progenitor cells
Authors: Buddika Kasun , Xu Jingjing , Ariyapala Ishara S. , Sokol Nicholas S.
Published: June 2020

The adult Drosophila intestinal epithelium is a model system for stem cell biology, but its utility is limited by current biochemical methods that lack cell type resolution. Here, we describe a new proximity-based profiling method that relies upon a GAL4 driver, termedintestinal-kickout-GAL4(I-KCKT-GAL4), exclusively expressed in intestinal progenitor cells. This method used UV cross-linked whole animal frozen powder as its starting material to immunoprecipitate the RNA cargoes of transgenic epitope-tagged RNA binding proteins driven byI-KCKT-GAL4. When applied to the general mRNA-binder, poly(A)-binding protein, the RNA profile obtained by this method identified 98.8% of transcripts found after progenitor cell sorting, and had low background noise despite being derived from whole animal lysate. We also mapped the targets of the more selective RNA binder, Fragile Mental Retardation Protein, using enhanced CLIP, and report for the first time its binding motif in Drosophila cells. This method will therefore enable the RNA profiling of wildtype and mutant intestinal progenitor cells from intact flies exposed to normal and altered environments, as well as the identification of RNA-protein interactions critical for stem cell function.

Summary Statement

We report a dissection-free method to identify proximity-based RNA-protein interactions in anin vivostem cell population, enabling molecular analysis of these cells at unprecedented speed and resolution.
LI Detector: a framework for sensitive colony-based screens regardless of the distribution of fitness effects
Authors: Parikh Saurin Bipin , Coelho Nelson Castilho , Carvunis Anne-Ruxandra
Published: June 2020

Microbial growth characteristics have long been used to investigate fundamental questions of biology. Colony-based high-throughput screens enable parallel fitness estimation of thousands of individual strains using colony growth as a proxy for fitness. However, fitness estimation is complicated by spatial biases affecting colony growth, including uneven nutrient distribution, agar surface irregularities, and batch effects. Analytical methods that have been developed to correct for these spatial biases rely on the following assumptions: i) that fitness effects are normally distributed, and ii) that most genetic perturbations lead to minor changes in fitness. Although reasonable for many applications, these assumptions are not always warranted and can limit the ability to detect small fitness effects. Beneficial fitness effects, in particular, are notoriously difficult to detect under these assumptions. Here, we developed the linear interpolation-based detector (LI Detector) framework to enable sensitive colony-based screening without making prior assumptions about the underlying distribution of fitness effects. The LI Detector uses a grid of reference colonies to assign a relative fitness value to every colony on the plate. We show that the LI Detector is effective in correcting for spatial biases and equally sensitive towards increase and decrease in fitness. LI Detector offers a tunable system that allows the user to identify small fitness effects with unprecedented sensitivity and specificity. LI Detector can be utilized to develop and refine gene-gene and gene-environment interaction networks of colony-forming organisms, including yeast, by increasing the range of fitness effects that can be reliably detected.
A collection of programs for one-dimensional Ising analysis of linear repeat proteins with point substitutions
Authors: Marold Jacob D. , Sforza Kevin , Geiger-Schuller Kathryn , Aksel Tural , Klein Sean , Petersen Mark , Poliakova-Georgantas Ekaterina , Barrick Doug
Published: June 2020

A collection of programs is presented to analyze the thermodynamics of folding of linear repeat proteins using a 1D Ising model to determine intrinsic folding and interfacial coupling free energies. Expressions for folding transitions are generated for a series of constructs with different repeat numbers and are globally fitted to transitions for these constructs. These programs are designed to analyze Ising parameters for capped homopolymeric consensus repeat constructs as well as heteropolymeric constructs that contain point substitutions, providing a rigorous framework for analysis of the effects of mutation on intrinsic and directional (i.e., N- versus C-terminal) interfacial coupling free-energies. A bootstrap analysis is provided to estimate parameter uncertainty as well as correlations among fitted parameters. Rigorous statistical analysis is essential for interpreting fits using the complex models required for Ising analysis of repeat proteins, especially heteropolymeric repeat proteins. Programs described here are available athttps://github.com/barricklab-at-jhu/Ising_programs.