bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of weather and increased atmospheric CO
2
from 1892 to 2016 on simulated yields of UK wheat
Authors: Addy John W. G. , Ellis Richard H. , Macdonald Andy J. , Semenov Mikhail A. , Mead Andrew
Published: June 2021

Climate change effects on UK winter wheat grain yield are complex: warmer temperature, negative; greater carbon dioxide (CO
2
) concentration, positive; but other environmental variables and their timing also affect yield. In the absence of long-term experiments where temperature and CO
2
concentration were manipulated separately, we applied the crop simulation model Sirius with long-term daily meteorological data (1892–2016) for Rothamsted, Hertfordshire, UK (2007–2016 mean growing season temperature 1.03°C warmer than 1892–1991), and CO
2
concentration over this period, to investigate the separate effects of historic CO
2
and weather on simulated grain yield in three wheat cultivars of the modern era. We show a slight decline in simulated yield over the period 1892–2016 from the effect of weather (daily temperature, rainfall and sunshine hours) at fixed CO
2
(294.50 ppm, 1892 reference value), but a maximum 9.4% increase when accounting for increasing atmospheric CO
2
(from 294.50 to 404.21 ppm), differing slightly among cultivars. Notwithstanding considerable inter-annual variation, the slight yield decline at 294.50 ppm CO
2
over this 125-year period from the historic weather simulations for Rothamsted agrees with the expected decline from temperature increase alone, but the positive yield trend with actual CO
2
values does not match the recent stagnation in UK wheat yield.
SIRT7: a sentinel of genome stability
Authors: Tang Ming , Tang Huangqi , Tu Bo , Zhu Wei-Guo
Published: June 2021

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.
Structural basis for the coiled-coil architecture of human CtIP
Authors: Morton C. R. , Rzechorzek N. J. , Maman J. D. , Kuramochi M. , Sekiguchi H. , Rambo R. , Sasaki Y. C. , Davies O. R. , Pellegrini L.
Published: June 2021

The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during the recombinational repair. The zinc-binding motif in the CtIP N-terminus alters dynamically the coiled-coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.
Journal of Medical Microbiology: global footprint and appointment of a regional Editorial Board
Authors: Mathee Kalai , Logan Hilary F. , Fry Norman K.
Published: June 2021

The Journal of Medical Microbiology has a global presence with an international Editorial Board. Asian countries such as PR China, India and Iran are prolific in the submission of manuscripts. Overall, the acceptance rate has been highest for European countries, the USA, Canada and Australia, and lowest for African, Asian and Latin American (LATAM) countries. The creation of regional Editors to assist the authors from these countries would serve the scientific community.
Targeted vaccination and the speed of SARS-CoV-2 adaptation
Authors: Gandon Sylvain , Lion Sébastien
Published: June 2021

The limited supply of vaccines against SARS-CoV-2 raises the question of targeted vaccination. Older and more sensitive hosts should be vaccinated first to minimize the disease burden. But what are the evolutionary consequences of targeted vaccination? We clarify the consequences of different vaccination strategies through the analysis of the speed of viral adaptation measured as the rate of change of the frequency of vaccine-escape mutations. We show that a vaccine-escape mutant is expected to spread faster if vaccination targets individuals which are likely to be involved in a higher number of contacts. We also discuss the pros and cons of dose-sparing strategies. Because delaying the second dose increases the proportion of the population vaccinated with a single dose, this strategy can both speed-up the spread of the vaccine-escape mutant and reduce the cumulated number of deaths. Hence, slowing down viral adaptation may not always be the optimal vaccination strategy. We contend that a careful assessment of the consequences of alternative vaccination strategies on both (i) the speed of adaptation and (ii) the mortality is required to determine which individuals should be vaccinated first.
Phase 1 Trial of Cyclosporine for Hospitalized Patients with COVID-19
Authors: Blumberg Emily A. , Tebas Pablo , Frank Ian , Marshall Amy , Chew Anne , Veloso Elizabeth A. , Carulli Alison , Rogal Walter , Gaymon Avery L. , Schmidt Aliza H. , Barnette Tiffany , Jurek Renee , Noorchashm Hooman , Hwang Wei-Ting , Noll Julia Han , Fraietta Joseph A. , June Carl H. , Hexner Elizabeth O.
Published: June 2021

Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses. To test whether a short course of treatment was safe in COVID-19 patients, we treated 10 hospitalized, oxygen requiring, non-critically ill patients with CSA at a starting dose of 9mg/kg/day. Five patients experienced adverse events, none were serious, and transaminitis was most common. No subject enrolled in this trial required intensive care unit (ICU)-level care and all patients were discharged alive from the hospital. Further, CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyper-inflammation, including CXCL10. In conclusion, short courses of CSA appear safe and feasible in COVID-19 patients requiring oxygen and therefore, may be a useful adjunct in resource-poor or resource-limited health care settings.
Chronic fatigue and post-exertional malaise in people living with long COVID
Authors: Twomey Rosie , DeMars Jessica , Franklin Kelli , Culos-Reed S. Nicole , Weatherald Jason , Wrightson James G.
Published: June 2021

Purpose

People living with long COVID describe a high symptom burden, and a more detailed assessment of chronic fatigue and post-exertional malaise (PEM) may inform the development of rehabilitation recommendations. The aims of this study were to use validated questionnaires to measure the severity of fatigue and compare this with normative data and thresholds for clinical relevance in other diseases; measure and describe the impact of PEM; and assess symptoms of dysfunctional breathing, self-reported physical activity/sitting time, and health-related quality of life.

Methods

This was an observational study involving an online survey for adults living with long COVID (data collection from February-April, 2021) following a confirmed or suspected SARS-CoV-2 infection. Questionnaires included the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) and DePaul Symptom Questionnaire-Post-Exertional Malaise.

Results

After data cleaning, n=213 participants were included in the analysis. Participants primarily identified as women (85.5%), aged 40-59 (78.4%), who had been experiencing long COVID symptoms for ≥6 months (72.3%). The total FACIT-F score was 18±10 (where the score can range from 0-52, and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Post-exertional symptom exacerbation affected most participants, and 58.7% met the scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome. PEM occurred alongside a reduced capacity to work, be physically active, and function both physically and socially.

Conclusion

Long COVID is characterized by chronic fatigue that is clinically relevant and is at least as severe as fatigue in several other clinical conditions, including cancer. PEM appears to be a common and significant challenge for the majority of this patient group. Patients, researchers, and allied health professionals are seeking information on safe rehabilitation for people living with long COVID, particularly regarding exercise. Fatigue and post-exertional symptom exacerbation must be monitored and reported in studies involving interventions for people with long COVID.
The NICE COVID-19 search strategy for Ovid MEDLINE and Embase: developing and maintaining a strategy to support rapid guidelines
Authors: Levay Paul , Finnegan Amy
Published: June 2021

Introduction
The United Kingdom's (UK) National Institute for Health and Care Excellence (NICE) needs access to evidence on COVID-19 to develop rapid guidelines for healthcare professionals. This paper reports on how the NICE COVID-19 search strategy for identifying references in Ovid MEDLINE and Embase has been developed and maintained.
Methods
Each free-text line from the June 2020 version of the NICE COVID-19 search strategy was categorised as Critical, High, Medium, Low or Zero priority, according to the number of results and their relevance to NICE. Five search options were devised and tested by combining them with a search for drug treatments. The two prioritised options were compared to the COVID-19 Limit available in Ovid. New subject headings were tested and added. The selected option was refined to make the strategy simpler to use.
Results
The updated strategy combines free-text terms, categorised as Critical, High and Medium priority for NICE, with appropriate subject headings.
Discussion
The paper describes the challenges of maintaining a search strategy during the COVID-19 pandemic, as terminology continues to evolve.
Conclusions
A search strategy for identifying COVID-19 references, within the remit of NICE, has been developed. The recommended strategy could be considered for validation at an appropriate point in the pandemic. It is hoped that understanding how NICE has maintained its COVID-19 strategy will encourage further discussion on the challenges.
Coupling freedom from disease principles and early warning from wastewater surveillance to improve health security
Authors: Larsen D. A. , Collins M. B. , Du Q. , Hill D. , Insaf T. Z. , Kilaru P. , Kmush B. L. , Middleton F. , Stamm A. , Wilder M. L. , Zeng T. , Green H.
Published: June 2021

Infectious disease surveillance is vitally important to maintaining health security, but these efforts are challenged by the pace at which new pathogens emerge. Wastewater surveillance can rapidly obtain population-level estimates of disease transmission, and we leverage freedom from disease principles to make use of non-detection of SARS-CoV-2 in wastewater to estimate the probability that a community is free from SARS-CoV-2 transmission. From wastewater surveillance of 24 treatment plants across upstate New York beginning in May 2020, we observed a reliable limit of detection of 0.3--0.5 cases per 10,000 population. No COVID-19 cases were reported 40% of the time following a non-detection of SARS-CoV-2 in wastewater, and cases were less than 1 daily case per 10,000 population 97% of the time following non-detection. Trends in the intensity of SARS-CoV-2 in wastewater correlate with trends in COVID-19 incidence and test positivity (ρ>0.5), with the greatest correlation observed for active cases and a three-day lead time between wastewater sample date and clinical test date. Wastewater surveillance can cost-effectively demonstrate the geographic extent of the transmission of emerging pathogens, confirming that transmission is absent or under control and alerting of an increase in transmission. If a statewide wastewater surveillance platform had been in place prior to the onset of the COVID-19 pandemic, policymakers would have been able to complement the representative nature of wastewater samples to individual testing, likely resulting in more precise public health interventions and policies.
The findings of Antimicrobial Resistance Surveillance in Bangladesh (2016-2020)
Authors: Habib Zakir Hossain , Golam Rasul Saima binte , Alam Md. Ashraful , Bably Nazmun Nahar , Khan Iqbal Ansary , Rizvi S.M. Shahriar , Shirin Tahmina , Alam Ahmed Nawsher , Uzzaman M. Salim , Alamgir ASM , Rahman Mahbubur , Reza Ashek Ahmmed Shahid , Ameen Kazi Mohammad Hassan , Muraduzzaman AKM , Siddiqui Ishrat , Haider Zarin Tasnim , Flora Meerjady Sabrina
Published: June 2021

Surveillance is one of the effective tools to address antimicrobial resistance. In Bangladesh a countrywide antimicrobial resistance surveillance has been ongoing since 2016. The main objective of this surveillance is to formulate the guideline for clinicians and to assist policy makers to know the gravity of the AMR problem in Bangladesh.

It is a case-based surveillance conducted by Institute of Epidemiology, Disease Control & Research (IEDCR) in nine sentinel sites where five types of clinical cases were selected according to case definition, and ten types of bacteria were identified from six types of preselected specimens. All the laboratory works were performed following the standard operating procedure supplied by the AMR surveillance Reference laboratory at IEDCR. Total 19,263 samples were processed during the period of March 2017 to March 2020 among which wound swab yielded highest growth (57%).E. coliwas the highest (1717) isolated organism among the ten priority pathogens which showed highest sensitivity (91%) to Imipenem. Imipenem also showed higher sensitivity to most of the organisms. Third generation cephalosporin was found to be less sensitive toEscherichia coli(37%) andKlebsiella pneumoniae(28%); nevertheless,Salmonellaspecies showed higher sensitivity (97%) to it.Acinetobacter calcoaceticus-baumannii complexisolated from ICU patients showed alarming resistance to all of the antibiotics including highest sensitive antibiotic Imipenem (29%).Salmonellaspecies isolated from blood showed higher susceptibility to most of the antibiotics except ciprofloxacin (7%). Alarmingly, only 36% of theStaphylococcus aureusisolates showed susceptibility to cefoxitin indicates high prevalence of MRSA infection.

The result of the surveillance representing the whole country is surely alarming as many of the bacteria are resistant to the commonly used as well as reserve groups of antibiotics. Concerted effort should be taken from all concerned authorities to curb the problem immediately.
Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup
Authors: Ben-Dov Iddo Z. , Oster Yonatan , Tzukert Keren , Alster Talia , Bader Raneem , Israeli Ruth , Asayag Haya , Aharon Michal , Burstein Ido , Pri-Chen Hadas , Imam Ashraf , Abel Roy , Levi Irit Mor-Yosef , Khalaileh Abed , Oiknine-Djian Esther , Bloch Aharon , Wolf Dana G. , Elhalel Michal Dranitzki
Published: June 2021

Background

Determining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

Methods

In a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results

175 dialysis patients (40% women, 65±15 years), 252 kidney transplant patients (33% women, 54±14 years) and 71 controls (65% women, 44±14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

Conclusions

Dialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

Significance

Reports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease.
Scaffold Protein RACK1 inhibitor compounds prevent the Focal Adhesion Kinase mediated breast cancer cell migration and invasion potential
Authors: Ullah Hemayet , Ahsan Nagib , Dakshanamurthy Sivanesan
Published: June 2021

Scaffold protein RACK1 mediates cancer cell migration mostly through regulation of focal adhesion (FA) assembly by promoting a focal adhesion kinase (FAK) activation downstream of the integrin clustering and adhesion at the extracellular matrix (ECM). Here we demonstrated the efficacy of our recently developed RACK1 Y246 phosphorylation inhibitor compounds (SD29 and SD29-14) to inhibit the migration and invasion of MCF7 and MDA-MB-231 breast cancer cell lines. Using multiple assays, our results confirmed that inhibitor compounds effectively prevent the filopodia/lamellipodia development and inhibits the migration of breast cancer cells. A mechanistic model of the inhibitor compounds has been developed. Migration and invasion capabilities of the cancer cells define the metastasis of cancer. Thus, our results suggest a potential therapeutic mechanism of the inhibitors to prevent metastasis in diverse cancers.
The atypical RNA-binding protein TAF15 regulates dorsoanterior neural development through diverse mechanisms in Xenopus tropicalis
Authors: DeJong Caitlin S. , Dichmann Darwin S. , Exner Cameron R. T. , Xu Yuxiao , Harland Richard M.
Published: June 2021

The FET family of atypical RNA-binding proteins includes Fused in sarcoma (Fus), Ewing’s sarcoma (EWS), and the TATA-binding protein-associate factor 15 (TAF15). FET proteins are highly conserved, suggesting specialized requirements for each protein. Fus regulates splicing of transcripts required for mesoderm differentiation and cell adhesion in Xenopus, but roles that EWS and TAF15 play remain unknown. Here we analyze the roles of maternally deposited and zygotically transcribed TAF15, which is essential for the proper development of dorsoanterior neural tissues. By measuring changes in exon usage and transcript abundance from TAF15-depleted embryos we found TAF15 may regulate dorsoanterior neural development through fgfr4 and ventx2.1. TAF15 uses distinct mechanisms to downregulate FGFR4 expression: 1) retention of a single intron within fgfr4 when maternal and zygotic TAF15 is depleted, and 2) reduction of total fgfr4 transcript when zygotic TAF15 alone is depleted. The two mechanisms of gene regulation (post-transcriptional vs transcriptional) suggest TAF15-mediated gene regulation is target and cofactor-dependent, depending on the milieu of factors that are present at different times of development.
Transcriptomic analysis of dorsal and ventral subiculum after induction of acute seizures by electric stimulation of the perforant pathway in rats
Authors: Aoyama Beatriz B. , Zanetti Gabriel G. , Dias Elayne V. , Athié Maria C. P. , Lopes-Cendes Iscia , Vieira André S.
Published: June 2021

Preconditioning is a mechanism in which injuries induced by non-lethal hypoxia or seizures trigger cellular resistance to subsequent events. Norwood et al., in a 2010 study, showed that an 8-hour-long period of electrical stimulation of the perforant pathway in rats is required for the induction of hippocampal sclerosis. However, in order to avoid generalized seizures, status epilepticus (SE), and death, a state of resistance to seizures must be induced in the hippocampus by a preconditioning paradigm consisting of 2 daily 30-minute stimulation periods. Due to the importance of the subiculum in the hippocampal formation, this study aims to investigate differential gene expression patterns in the dorsal and ventral subiculum using RNA-sequencing, after induction of a preconditioning protocol by electrical stimulation of the perforant pathway. The dorsal (dSub) and ventral (vSub) subiculum regions were collected by laser-microdissection 24 hours after preconditioning protocol induction in rats. RNA sequencing was performed in a Hiseq 4000 platform, reads were aligned using the STAR and DESEq2 statistics package was used to estimate gene expression. We identified 1176 differentially expressed genes comparing control to preconditioned subiculum regions, 204 genes were differentially expressed in dSub and 972 in vSub. The gene ontology enrichment analysis showed that the most significant common enrichment pathway considering up-regulated genes in dSub and vSub was Cholesterol Biosynthesis. In contrast, the most significant enrichment pathway considering down-regulated genes in vSub was Axon guidance. Our results indicate that preconditioning induces synaptic reorganization, increased cholesterol metabolism, and astrogliosis in both dSub and vSub. Both regions also presented a decrease in glutamatergic transmission, an increase in complement system activation, and increased in GABAergic transmission. The down-regulation of proapoptotic and axon guidance genes in the ventral subiculum suggests that preconditioning induces a neuroprotective environment in this region.
Gui Shao Di Huang Wan promotes angiogenesis and regulates oestrogen receptor α and progesterone receptor β in in vitro bioassays
Authors: O’Cleirigh Rebecca , Gibbs Roslyn
Published: June 2021

Background and aim

The formula Gui Shao Di Huang Wan (GSDW) is used frequently to treat female infertility. This study aims to investigate some of the possible mechanisms of action of GSDW using in vitro bioassays of angiogenesis in Human Uterine Microvascular Endothelial Cells (HUVEC) and Human Uterine Microvascular Endothelial Cells (HUtMEC) and ovarian steroid receptor expression in a human endometrial cell line (Ishikawa).

Experimental procedure

Aqueous extracts of GSDW and its component herbs were tested for pro-angiogenic activity using both HUVEC and HUtMEC 2D differentiation assays performed on Matrigel and effects on HUVEC proliferation using the MTT assay. Effects on the expression of Estrogen Receptor α (ERα) and Progesterone Receptor β (PRβ) in Ishikawa cells were determined using immunoblotting.

Results and Conclusion

All analysed parameters of differentiation were increased by GSDW in both the HUVEC and HUtMEC mesh. Furthermore, measures of total length, segment number, junction number were affected by some but not all component herbs.

The MTT assay showed an increase in proliferation of HUVECs at concentrations of GSDW between 0.68 and 5.47 μg/mL at 48 and 72 hours.

In Ishikawa cells downregulation of ERα and upregulation of PRβ was seen after 48 hours incubation with 4 of the 8 herbs in the formula.

The findings in this study demonstrate that GSDW has the potential to affect key parameters (vascular, sex hormone receptor expression) in vitro. This offers a mechanism by which these herbs may enhance fertility through improved endometrial receptivity and pregnancy rates.
Peroxisomal ATP uptake is managed by the ABC transporters and two adenine nucleotide transporters
Authors: van Roermund Carlo , IJlst Lodewijk , Linka Nicole , Wanders Ronald J.A. , Waterham Hans R.
Published: June 2021

Peroxisomes are essential organelles involved in various metabolic processes, including fatty acid β-oxidation. Their metabolic functions require a controlled exchange of metabolites and co-factors, including ATP across the peroxisomal membrane. We investigated which proteins are involved in the peroxisomal uptake of ATP in the yeast Saccharomyces cerevisiae. Using wild-type and targeted deletion strains, we measured ATP-dependent peroxisomal octanoate β-oxidation, intra-peroxisomal ATP levels employing peroxisome-targeted ATP-sensing reporter proteins, and ATP uptake in proteoliposomes prepared from purified peroxisomes. We show that intra-peroxisomal ATP levels are maintained by different peroxisomal membrane proteins each with different modes of action: (1) the previously reported Ant1p protein, which catalyzes ATP/AMP exchange (2) the ABC transporter protein complex Pxa1p/Pxa2p, which mediates both acyl-CoA and ATP uptake; and; (3) the mitochondrial Aac2p protein, which catalyzes ATP/ADP exchange and was shown to have a dual localization in both mitochondria and peroxisomes. Our results provide compelling evidence for an ingenious complementary system for the uptake of ATP in peroxisomes.
Regulation Network of Colorectal Cancer Specific Enhancers in Progression of Colorectal Cancer
Authors: Chen Bohan , Ma Yiping , Bi Jinfang , Wang Wenbin , He Anshun , Su Guangsong , Zhao Zhongfang , Shi Jiandang , Zhang Lei
Published: June 2021

Enhancers regulate multiple genes through higher-order chromatin structure and further affect cancer progression. Epigenetic changes in cancer cells activate several cancer specific enhancers that are silenced in normal cells. These cancer specific enhancers are potential therapeutic targets of cancer. However, functions and regulation network of colorectal cancer specific enhancers are still unknown. Here in this study, we profile colorectal cancer specific enhancers and reveal the regulation network of these enhancers by analysis of HiChIP, Hi-C and RNA-seq data. We propose the regulation network of colorectal cancer specific enhancers plays important role in progression of colorectal cancer.
High resolution dynamic mapping of the C. elegans intestinal brush border
Authors: Bidaud-Meynard Aurélien , Demouchy Flora , Nicolle Ophélie , Pacquelet Anne , Suman Shashi Kumar , Plancke Camille , Robin François , Michaux Grégoire
Published: June 2021

The intestinal brush border is made of an array of microvilli that increases the membrane surface area for nutrient processing, absorption, and host defence. Studies on mammalian cultured epithelial cells uncovered some of the molecular players and physical constrains required to establish this apical specialized membrane. However, the building and maintenance of a brush border in vivo has not been investigated in detail yet. Here, we combined super-resolution imaging, transmission electron microscopy and genome editing in the developing nematode C. elegans to build a high-resolution and dynamic localization map of known and new markers of the brush border. Notably, we show that microvilli components are dynamically enriched at the apical membrane during microvilli outgrowth and maturation but become highly stable once microvilli are built. This new mapping tool will be instrumental to understand the molecular processes of microvilli growth and maintenance in vivo as well as the effect of genetic perturbations, notably in the context of disorders affecting brush border integrity.
Sniffing Out New Friends: Similarity in Body-Odor Predicts the Quality of Same-Sex Non-Romantic Dyadic Interactions
Authors: Ravreby Inbal , Snitz Kobi , Sobel Noam
Published: June 2021

Most are familiar with the notion of socially “clicking” with someone, namely sensing an immediate bond that can lead to strong and often long-lasting friendships. The mechanisms underlying such rapid bonding remain unclear. Given that body-odor similarity is a critical cue for social interaction in non-human mammals, we tested the hypothesis that body-odor similarly contributes to bonding in same-sex non-romantic human dyads. We observed that objective ratings obtained with an electronic nose, and subjective ratings obtained from human smellers, converged to suggest that click-friends smell more similar to each other than random dyads. Remarkably, we then found that we could use the electronic nose to predict which strangers would later form better dyadic interactions. Thus, humans may literally sniff-out new friends based on similarities in body-odor.
Selective nuclear export of mRNAs is promoted by DRBD18 in Trypanosoma brucei
Authors: Mishra Amartya , Kaur Jan Naseer , McSkimming Daniel I. , Hegedusova Eva , Dubey Ashutosh P. , Ciganda Martin , Paris Zdenek , Read Laurie K.
Published: June 2021

Kinetoplastids, including Trypanosoma brucei, control gene expression primarily at the posttranscriptional level. Nuclear mRNA export is an important, but understudied, step in this process. The general heterodimeric export factors, Mex67/Mtr2, function in the export of mRNAs and tRNAs in T. brucei, but RNA binding proteins (RBPs) that regulate export processes by controlling the dynamics of Mex67/Mtr2 ribonucleoprotein formation or transport have not been identified. Here, we report that DRBD18, an essential and abundant T. brucei RBP, associates with Mex67/Mtr2 in vivo, likely through its direct interaction with Mtr2. DRBD18 downregulation results in partial accumulation of poly(A)+ mRNA in the nucleus, but has no effect on localization of intron-containing or mature tRNAs. Comprehensive analysis of transcriptomes from whole cell and cytosol in DRBD18 knockdown parasites demonstrates that depletion of DRBD18 leads to impairment of nuclear export of a subset of mRNAs. CLIP experiments reveal association of DRBD18 with several of these mRNAs. Moreover, DRBD18 knockdown leads to a partial accumulation of the Mex67/Mtr2 export receptors in the nucleus. Taken together, the current study supports a model in which DRBD18 regulates the selective nuclear export of mRNAs by promoting the mobilization of export competent mRNPs to the cytosol through the nuclear pore complex.
Evolution of the nitric oxide synthase family in vertebrates and novel insights in gill development
Authors: Annona Giovanni , Sato Iori , Pascual-Anaya Juan , Braasch Ingo , Voss Randal , Stundl Jan , Soukup Vladimir , Kuratani Shigeru , Postlethwait John H. , D’Aniello Salvatore
Published: June 2021

Nitric oxide (NO) is an ancestral key signaling molecule essential for life and has enormous versatility in biological systems, including cardiovascular homeostasis, neurotransmission, and immunity. Although our knowledge of nitric oxide synthases (Nos), the enzymes that synthesize NO in vivo, is substantial, the origin of a large and diversified repertoire of nos gene orthologs in fish with respect to tetrapods remains a puzzle. The recent identification of nos3 in the ray-finned fish spotted gar, which was considered lost in the ray-finned fish lineage, changed this perspective. This prompted us to explore nos gene evolution and expression in depth, surveying vertebrate species representing key evolutionary nodes. This study provides noteworthy findings: first, nos2 experienced several lineage-specific gene duplications and losses. Second, nos3 was found to be lost independently in two different teleost lineages, Elopomorpha and Clupeocephala. Third, the expression of at least one nos paralog in the gills of developing shark, bichir, sturgeon, and gar but not in arctic lamprey, suggest that nos expression in this organ likely arose in the last common ancestor of gnathostomes. These results provide a framework for continuing research on nos genes’ roles, highlighting subfunctionalization and reciprocal loss of function that occurred in different lineages during vertebrate genome duplications.
Enhanced processing of aversive stimuli on embodied artificial limbs by the human amygdala
Authors: Fourcade Antonin , Schmidt Timo Torsten , Nierhaus Till , Blankenburg Felix
Published: June 2021

Body perception has been extensively investigated, with one particular focus being the integration of vision and touch within a neuronal body representation. Previous studies have implicated a distributed network comprising the extrastriate body area (EBA), posterior parietal cortex (PPC) and ventral premotor cortex (PMv) during illusory self-attribution of a rubber hand. Here, we set up an fMRI paradigm in virtual reality (VR) to study whether and how threatening (artificial) body parts affects their self-attribution. Participants (N=30) saw a spider (aversive stimulus) or a toy-car (neutral stimulus) moving along a 3D-rendered virtual forearm positioned like their real forearm, while tactile stimulation was applied on the real arm in the same (congruent) or opposite (incongruent) direction. We found that the PPC was more activated during congruent stimulation; higher visual areas and the anterior insula (aIns) showed increased activation during aversive stimulus presentation; and the amygdala was more strongly activated for aversive stimuli when there was stronger multisensory integration of body-related information (interaction of aversiveness and congruency). Together, these findings suggest an enhanced processing of aversive stimuli within the amygdala when they represent a bodily threat.
Modularity and selection of nectar traits in the evolution of the selfing syndrome inIpomoea lacunosa(Convolvulaceae)
Authors: Liao Irene T. , Rifkin Joanna L. , Cao Gongyuan , Rausher Mark D.
Published: June 2021

Although the evolution of the selfing syndrome often involves reductions in floral size, pollen, and nectar, few studies of selfing syndrome divergence have examined nectar. We investigate whether nectar traits have evolved independently of other floral size traits in the selfing syndrome, whether nectar traits diverged due to drift or selection, and the extent to which quantitative trait locus (QTL) analyses predict genetic correlations.

We use F5 recombinant inbred lines (RILs) generated from a cross betweenIpomoea cordatotrilobaandI. lacunosa. We calculate genetic correlations to identify evolutionary modules, test whether traits have been under selection, identify QTLs, and perform correlation analyses to evaluate how well QTL properties reflect the genetic correlations.

Nectar and floral size traits form separate genetic clusters. Directional selection has acted to reduce nectar traits in the selfingI. lacunosa. Calculations from QTL properties are consistent with observed genetic correlations.

Floral trait divergence during mating system syndrome evolution reflects independent evolution of at least two evolutionary modules: nectar and floral size traits. This independence implies that adaptive change in these modules requires direct selection on both floral size and nectar traits. Our study also supports the expected mechanistic link between QTL properties and genetic correlations.
Accurate prediction of protein structures and interactions using a 3-track network
Authors: Baek Minkyung , DiMaio Frank , Anishchenko Ivan , Dauparas Justas , Ovchinnikov Sergey , Lee Gyu Rie , Wang Jue , Cong Qian , Kinch Lisa N. , Schaeffer R. Dustin , Millán Claudia , Park Hahnbeom , Adams Carson , Glassman Caleb R. , DeGiovanni Andy , Pereira Jose H. , Rodrigues Andria V. , van Dijk Alberdina A. , Ebrecht Ana C. , Opperman Diederik J. , Sagmeister Theo , Buhlheller Christoph , Pavkov-Keller Tea , Rathinaswamy Manoj K , Dalwadi Udit , Yip Calvin K , Burke John E , Garcia K. Christopher , Grishin Nick V. , Adams Paul D. , Read Randy J. , Baker David
Published: June 2021

DeepMind presented remarkably accurate protein structure predictions at the CASP14 conference. We explored network architectures incorporating related ideas and obtained the best performance with a 3-track network in which information at the 1D sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The 3-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables rapid solution of challenging X-ray crystallography and cryo-EM structure modeling problems, and provides insights into the functions of proteins of currently unknown structure. The network also enables rapid generation of accurate models of protein-protein complexes from sequence information alone, short circuiting traditional approaches which require modeling of individual subunits followed by docking. We make the method available to the scientific community to speed biological research.

One-Sentence Summary

Accurate protein structure modeling enables rapid solution of structure determination problems and provides insights into biological function.
Mouse models of immune dysfunction: Their neuroanatomical differences reflect their anxiety-behavioural phenotype
Authors: Fernandes Darren J. , Spring Shoshana , Corre Christina , Tu Andrew , Qiu Lily R. , Hammill Christopher , Vousden Dulcie A. , Noakes T. Leigh Spencer , Nieman Brian J. , Bowdish Dawn M.E , Foster Jane A. , Palmert Mark R. , Lerch Jason P.
Published: June 2021

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging (MRI), we studied the neuroanatomical differences among 11 distinct genetically-modified mouse lines (n=371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures -- such as the corpus callosum, midbrain, and thalamus -- were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.
Harnessing the power of metabarcoding in the ecological interpretation of plant-pollinator DNA data: strategies and consequences of reads filtering
Authors: Tommasi Nicola , Ferrari Andrea , Labra Massimo , Galimberti Andrea , Biella Paolo
Published: June 2021

DNA metabarcoding approaches to analyse complex mixtures of pollen has become the standard in pollination biology, especially in the light of recent threats affecting pollination. In spite of the increasing adoption of High Throughput Sequencing (HTS) approaches, these studies generate huge numbers of raw reads, some of which might be associated to false positives or infrequently recorded species with potentially little biological information. If these reads are not discarded (i.e. pruned), they can lead to changes in the ecological findings and lead to biased conclusions. In this study we reviewed 42 papers in the recent pollen DNA metabarcoding literature and focused on the type of pruning applied. We also tested whether the different types of those cut off threshold may leave a mark on the DNA metabarcoding data. To do so, we compared for the first time community composition, species richness and networks of species interactions (i.e. Connectace, Modularity, Connectivity and Shannon entropy) associated with the most relevant ways of treating HTS outputs: no cut (no reads filtering), or cutting levels obtained as proportional 1% of sample total reads, or as fixed amount of 100 reads, or from ROC (Receiver operator characteristic). Results clearly indicated that pruning type shapes species composition and that to apply or not a threshold dramatically impacts ecological indices, potentially increasing the risk of misinterpreting DNA metabarcoding data under an ecological point of view. Given the high methodological heterogeneity from the revised literature, we discuss in what conditions filtering types may be more appropriate, and also recommend to biologically justify the pruning threshold when analysing DNA metabarcoding raw reads, and to develop shared approaches to make future studies more comparable.
Stepwise evolution and exceptional conservation of ORF1a/b overlap in coronaviruses
Authors: Mei Han , Nekrutenko Anton
Published: June 2021

The programmed frameshift element (PFE) rerouting translation fromORF1atoORF1bis essential for propagation of coronaviruses. A combination of genomic features that make up PFE—the overlap between the two reading frames, a slippery sequence, as well as an ensemble of complex secondary structure elements—puts severe constraints on this region as most possible nucleotide substitution may disrupt one or more of these elements. The vast amount of SARS-CoV-2 sequencing data generated within the past year provides an opportunity to assess evolutionary dynamics of PFE in great detail. Here we performed a comparative analysis of all available coronaviral genomic data available to date. We show that the overlap betweenORF1aandbevolved as a set of discrete 7, 16, 22, 25, and 31 nucleotide stretches with a well defined phylogenetic specificity. We further examined sequencing data from over 350,000 complete genomes and 55,000 raw read datasets to demonstrate exceptional conservation of the PFE region.
seqgra: Principled Selection of Neural Network Architectures for Genomics Prediction Tasks
Authors: Krismer Konstantin , Hammelman Jennifer , Gifford David K.
Published: June 2021

Sequence models based on deep neural networks have achieved state-of-the-art performance on regulatory genomics prediction tasks, such as chromatin accessibility and transcription factor binding. But despite their high accuracy, their contributions to a mechanistic understanding of the biology of regulatory elements is often hindered by the complexity of the predictive model and thus poor interpretability of its decision boundaries. To address this, we introduce seqgra, a deep learning pipeline that incorporates the rule-based simulation of biological sequence data and the training and evaluation of models, whose decision boundaries mirror the rules from the simulation process. The method can be used to (1) generate data under the assumption of a hypothesized model of genome regulation, (2) identify neural network architectures capable of recovering the rules of said model, and (3) analyze a model’s predictive performance as a function of training set size, noise level, and the complexity of the rules behind the simulated data.
Finding priority ribosomes for future structural and pathogen research based upon global RNA and protein sequence analysis
Authors: Cooper Helena B. , Krause Kurt L. , Gardner Paul P.
Published: June 2021

Ribosome-targeting antibiotics comprise over half of antibiotics used in medicine, but our fundamental knowledge of their binding sites is derived primarily from ribosome structures from non-pathogenic species. These include Thermus thermophilus, Deinococcus radiodurans and Haloarcula marismortui, as well as commensal and pathogenic Escherichia coli. Advancements in electron cryomicroscopy have allowed for the determination of more ribosome structures from pathogenic bacteria, with each study highlighting species-specific differences that had not been observed in the non-pathogenic structures. These observed differences suggest that more novel ribosome structures, particularly from pathogens, are required for a more accurate understanding of the level of diversity of the entire bacterial ribosome, potentially leading to potential advancements in antibiotic research. In this study, high accuracy covariance and hidden Markov models were used to annotate ribosomal RNA and protein sequences respectively from genomic sequence, allowing us to determine the underlying ribosomal sequence diversity using phylogenetic methods. This analysis provided evidence that the current non-pathogenic ribosome structures are not sufficient representatives of some pathogenic bacteria, such as Campylobacter pylori, or of whole phyla such as Bacteroidetes.

Significance Statement

The growing number of antibiotic resistance pathogenic bacteria are of critical concern to the health profession. Many of the current classes of antibiotics target the bacterial ribosome, the protein making factory for these species. However, much of our knowledge of the bacterial ribosome is based upon non-pathogenic bacteria that are highly divergent from the major pathogens of concern. We have analysed the genetic variation of the RNA and protein components of all available bacterial ribosomes. This has led us to identify the highest priority groups of bacteria that would benefit most from further analysis of their ribosome structures, from both a medical and evolutionary perspective.