bluuebunny/crossref_metadata_2025 huggingface dataset:
On folding morphogenesis, a mechanical problem
Authors: Tozluoǧlu Melda , Mao Yanlan
Published: August 2020

Tissue folding is a fundamental process that sculpts a simple flat epithelium into a complex three-dimensional organ structure. Whether it is the folding of the brain, or the looping of the gut, it has become clear that to generate an invagination or a fold of any form, mechanical asymmetries must exist in the epithelium. These mechanical asymmetries can be generated locally, involving just the invaginating cells and their immediate neighbours, or on a more global tissue-wide scale. Here, we review the different mechanical mechanisms that epithelia have adopted to generate folds, and how the use of precisely defined mathematical models has helped decipher which mechanisms are the key driving forces in different epithelia.

This article is part of a discussion meeting issue ‘Contemporary morphogenesis'.
Identification ofMYOM2as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot and its functional evaluation in theDrosophilaheart
Authors: Auxerre-Plantié Emilie , Nielsen Tanja , Grunert Marcel , Olejniczak Olga , Perrot Andreas , Özcelik Cemil , Harries Dennis , Matinmehr Faramarz , Remedios Cristobal Dos , Mühlfeld Christian , Kraft Theresia , Bodmer Rolf , Vogler Georg , Sperling Silke R.
Published: August 2020

The causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in theDrosophilaanimal model reveal that the so far uncharacterized fly geneCG14964may be an ortholog ofMYOM2, as well as other myosin binding proteins (henceforth named asDrosophilaMyomesin andMyosin Binding protein (dMnM)). Its partial loss-of-function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations ofCG14964and the sarcomere geneMhc(MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest thatMYOM2not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.

SUMMARY STATEMENT

MYOM2plays a critical role in establishing or maintaining robust heart function and is a candidate gene for heart diseases such as hypertrophic cardiomyopathy and Tetralogy of Fallot.
The medakaalg2mutant is a model for hypo-N-glycosylation-associated retinitis pigmentosa
Authors: Gücüm Sevinç , Sakson Roman , Hoffmann Marcus , Grote Valerian , Beedgen Lars , Thiel Christian , Rapp Erdmann , Ruppert Thomas , Wittbrodt Joachim , Thumberger Thomas
Published: August 2020

Patients suffering from Congenital Disorders of Glycosylation (CDG) carry mutations in components of the evolutionarily highly conserved protein-glycosylation-machinery. Employing targeted genome editing, we modeled alleles in medaka fish based on a mutation described in an ALG2-index patient. The multisystemic phenotypes in ouralg2model closely resembled the patient’s syndromes. Molecularly, the mutation results in a reduction of the abundance ofN-glycans without altering the profile of glycan structures in fish as well as in patient fibroblasts. This hypo-N-glycosylation impacted on protein abundance in two directions. We discovered a putative compensatory upregulation of the basic glycosylation and glycoprotein processing machinery highlighting the regulatory topology of the network. Conversely, proteins of the retinal phototransduction machinery were massively downregulated in thealg2model. Those relate to the specific loss of rod photoreceptors that fail to be maintained in thealg2mutants, a condition known as retinitis pigmentosa. Transient supply of human or medakaalg2mRNA efficiently rescued the phenotypic spectrum and restored viability demonstrating that ouralg2model delivers key traits for the potential treatment of the disorder.
SARS-CoV-2 infection and transmission in educational settings: cross-sectional analysis of clusters and outbreaks in England
Authors: Ismail Sharif A , Saliba Vanessa , Lopez Bernal Jamie , Ramsay Mary E , Ladhani Shamez N
Published: August 2020

Background

There are limited data on SARS-CoV-2 infection and transmission in educational settings. This information is critical for policy makers and practitioners to ensure the safety of staff, students and the wider community during the COVID-19 pandemic.

Methods

Public Health England initiated enhanced national surveillance following the reopening of educational settings during the summer mini-term on 01 June 2020. COVID-19 related situations in educational settings across England were reviewed daily and followed-up until 31 July 2020. SARS-CoV-2 infection and outbreak rates were calculated for staff and students attending early year settings, primary and secondary schools during June 2020.

Findings

There were 67 single confirmed cases, 4 co-primary cases and 30 COVID-19 outbreaks during June 2020, with a strong correlation between number of outbreaks and regional COVID-19 incidence (0.51 outbreaks for each SARS-CoV-2 infection per 100,000 in the community; p=0.001). Overall, SARS-CoV-2 infections and outbreaks were uncommon across all educational settings. Staff members had an increased risk of SARS-CoV-2 infections compared to students in any educational setting, and the majority of cases linked to outbreaks were in staff. The probable transmission direction for the 30 confirmed outbreaks was: staff-to-staff (n=15), staff-to-student (n=7), student-to-staff (n=6) and student-to-student (n=2).

Interpretation

SARS-CoV-2 infections and outbreaks were uncommon in educational settings during the first month after the easing of national lockdown in England. The strong correlation with regional SARS-CoV-2 incidence emphasises the importance of controlling community transmission to protect educational settings. Additional interventions should focus on reducing transmission in and among staff members.

Funding

none
Prognostic and theragnostic biomarkers in ovarian clear cell carcinoma
Authors: Wiedemeyer Katharina , Wang Linyuan , Kang Eun Young , Liu Shuhong , Ou Young , Kelemen Linda E. , Feil Lukas , Anglesio Michael S. , Glaze Sarah , Ghatage Prafull , Nelson Gregg S. , Köbel Martin
Published: August 2020

In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theragnostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in-situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theragnostic biomarkers (ALK, BRAF, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-year ovarian cancer specific survival of 33.3%, compared to 91.5% in the other stage I cases). Among theragnostic targets,ERBB2amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. Additionally, OCCC could be tested forERBB2amplification for inclusion in gynecological basket trials targeting this alteration.
Distinct mutational profile of Lynch syndrome colorectal cancers diagnosed under regular colonoscopy surveillance
Authors: Ahadova Aysel , Pfuderer Pauline L. , Ahtiainen Maarit , Ballhausen Alexej , Bohaumilitzky Lena , Kösegi Svenja , Müller Nico , Tang Yee Lin , Kosmalla Kosima , Witt Johannes , Endris Volker , Stenzinger Albrecht , von Knebel Doeberitz Magnus , Bläker Hendrik , Renkonen-Sinisalo Laura , Lepistö Anna , Böhm Jan , Mecklin Jukka-Pekka , Seppälä Toni T. , Kloor Matthias
Published: August 2020

Background

Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers).

Methods

We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high through-put coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs.

Results

Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p< 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lowerKRAScodon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenicTP53mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncatingAPCmutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018).

Conclusions

LS CRC diagnosed under regular colonoscopy surveillance are biologically distinct, suggesting that the preventive effectiveness of colonoscopy in LS depends on the molecular subtypes of tumors.
Randomized Controlled Trials of Remdesivir in Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis
Authors: Sarfraz Azza , Sarfraz Zouina , Sanchez-Gonzalez Marcos , Michel Jack , Michel George , Frontela Odalys , Posado Jorge , Cardona Jose , Angueira Eugonia
Published: August 2020

Background

The first cases of the coronavirus disease 2019 (COVID-19) were reported in Wuhan, China. No antiviral treatment options are currently available with proven clinical efficacy. However, preliminary findings from phase III trials suggest that remdesivir is an effective and safe treatment option for COVID-19 patients with both moderate and severe disease.

Objective

The aim of the present meta-analysis was to investigate whether remdesivir was effective for treating COVID-19 including reduced in-hospital adverse events, oxygen support, and mortality rates.

Methods

According to PRISMA reporting guidelines, a review was conducted from January 1 2020 until 25 August 2020 with MeSH terms including COVID-19, COVID, coronavirus, SARS-CoV-2, remdesivir, adenosine nucleoside triphosphate analog, Veklury using MEDLINE, Scopus, and CINAHL Plus. A modified Delphi process was utilized to include the studies and ensure that the objectives were addressed. Using dichotomous data for select values, the unadjusted odds ratios (ORs) were calculated applying Mantel Haenszel (M-H) random-effects method in Review Manager 5.4.

Results

Randomized controlled trials pooled in 3013 participants with 46.3% (n=1,395) in the remdesivir group and 53.7% (n=1,618) in the placebo group. The placebo group had a higher risk of mortality as compared to the intervention group with significant odds ratio (OR=0.61) (95% confidence interval of 0.45 0.82; P=0.001). There was minimal heterogeneity among the studies (I2=0%).

Conclusions

Our findings suggest that remdesivir extends clinical benefits by reducing mortality, adverse events and oxygen support in moderate to severely ill COVID-19 patients. Concerted efforts and further randomized placebo-controlled trials are warranted to examine the potency of antiviral drugs and immune-pathological host responses contributing to severity of COVID-19.
Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis
Authors: Campbell Cori , Wang Tingyan , McNaughton Anna , Barnes Eleanor , Matthews Philippa C
Published: August 2020

Background

Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is the largest cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is not certain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore we performed a systematic review and meta-analysis to seek evidence for significant associations.

Methods

MEDLINE, Embase and Web of Science databases were searched from 1stJanuary 2000 to 24thJune 2020 for English studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection. We extracted data for meta-analysis and report pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present.

Results

We identified 40 observational studies reporting on associations of diabetes mellitus, hypertension, dyslipiaemia and obesity with HCC risk. Meta-analysis was possible for only diabetes mellitus due to the limited number of studies. Diabetes mellitus was associated with > 25% increase in hazards of HCC (fixed effects Hazards Ratio [HR] 1.26, 95% CI 1.20–1.32, random effects HR 1.36, 95% CI 1.23–1.49). This association was attenuated towards the null in sensitivity analysis restricted to studies adjusted for metformin use.

Conclusions

In adults with chronic HBV infection, diabetes mellitus is a significant risk factor for HCC, but further investigation of how antidiabetic drug use and glycaemic control influence this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.
Health Disparities and COVID-19: A Retrospective Study Examining Individual and Community Factors Causing Disproportionate COVID-19 Outcomes in Cook County, Illinois, March 16-May 31, 2020
Authors: Unruh Larissa H , Dharmapuri Sadhana , Yinglin Xia , Soyemi Kenneth
Published: August 2020

Background

Early data from the COVID-19 pandemic suggests that the disease has had a disproportionate impact on communities of color causing higher infection and mortality rates within those communities.

Methods

This study used demographic data from the 2018 US census estimates, mortality data from the Cook County Medical Examiner’s office, and testing results from the Illinois Department of Public Health to perform both bivariate and multivariate regression analyses to explore the role race plays in COVID-19 outcomes at the individual and community levels.

Results

Principal findings show that: 1) while Black Americans make up 22% of Cook County’s population, they account for 36% of the county’s COVID-19 related deaths; 2) the average age of death from COVID-19 is seven years younger for minorities compared to Non-Hispanic White (White) decedents; 3) minorities were more likely than Whites to have seven of the top 10 co-morbidities at death; 4) residents of predominantly minority areas were twice as likely to test positive for COVID-19 (p = 0.0001, IRR 1.94, 95% CI 1.50, 2.50) than residents of predominantly White areas; and 5) residents of predominantly minority areas were 1.43 times more likely to die of COVID-19 than those in predominantly White areas (p = 0.03).

Conclusions

There are notable differences in COVID-19 related outcomes between racial and ethnic groups at individual and community levels. We hope that this study will scientifically illustrate the health disparities experienced by communities of color and help to address the underlying systemic inequalities still prevalent within our country.
Racial/Ethnic and Economic Segregation and Survival in the United States
Authors: Mejía-Guevara I. , Cullen M.R. , Tuljapurkar S. , Periyakoil V.S. , Rehkopf D.
Published: August 2020

Life expectancy differences across racial/ethnic and economic groups persist in the U.S., but little is known about the combined effects of racial and income segregation in explaining old age survival across neighborhoods. We operationalized neighborhoods using census tracts, with 65,655 of them nested within 3,015 counties, nested within 49 states. We linked census track life table data for ages 45-74 (n=196,965) from the National Vital Statistics System with 5-year population estimates (2011-2015) stratified by race/ethnicity and income from the American Community Survey. We measured racial/ethnic and income segregation using the Index of Concentration of the Extremes at the census tract level, and the indexes of dissimilarity and exposure at the county level. Using three-level random intercept models, we assessed the direct and contextual relationship between survival at ages 45-74 with racial/ethnic and income segregation. Regardless of racial/ethnic stratification, a high concentration of neighborhood poverty was associated with a lower probability of survival relative to affluent neighborhoods (−4.83%; 95% CI −4.86, −4.79), although the relationship was larger in neighborhoods with high concentration of Blacks (−5.61%; −5.67, −5.54). Black-white county-level unevenness also had the largest negative association in those neighborhoods (−0.26%; −0.32, −0.20). Furthermore, Black isolation was negatively associated with a lower survival probability (−0.21%; −0.29, −0.13), but Hispanic isolation was positively associated (0.23%; 0.16, 0.30). Opposite relationships resulted from Black-White (0.06; −0.01, 0.14) and Hispanic-White (−0.13; −0.21, −0.05) interactions. Finally, high exposure to neighborhood poverty/affluence was associated with lower/higher probability of neighborhood survival, but the associations were the strongest for Blacks.

Significance

Racial/ethnic and income residential segregation have been associated with negative health outcomes and increased risk of mortality in the U.S. We tested the association between residential segregation at different geographic levels with the survival probability at ages 45-74 across rural/urban neighborhoods. Results indicate that the racial/ethnic and income geographic composition of the population are important factors for explaining this relationship. That is, poverty concentration, minority-white unevenness, and exposure to poverty, had detrimental outcomes for all communities, irrespective of their racial/ethnic composition. However, while minority-isolation/-exposure to whites is detrimental/protective for Black communities, the opposite happened in Hispanic communities. Our research provides important insights in understanding the extent to which residential segregation explains survival disparities across neighborhoods based on their race/ethnicity composition.
Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance
Authors: Scalzo Rebecca L. , Foright Rebecca M. , Hull Sara E. , Knaub Leslie A. , Johnson-Murguia Stevi , Kinanee Fotobari , Kaplan Jeffrey , Freije Benjamin , Verzosa Gregory , Houck Julie A. , Johnson Ginger , Zhang Anni M.Y. , Johnson James D. , MacLean Paul S. , Reusch Jane E.B. , Wright-Hobart Sabrina , Wellberg Elizabeth A.
Published: August 2020

Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use associated with larger breast adipocyte diameter only in women with a BMI >30 kg/m2. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression ofEsr1observed in single-cell RNA sequencing of mesenchymal stem cells from adipose tissue, endocrine therapies induced adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. Metformin or pioglitazone, glucose lowering drugs used to treat diabetes, prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies act via ERα to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.
Relabeling metabolic pathway data with groups to improve prediction outcomes
Authors: Basher Abdur Rahman M. A. , Hallam Steven J.
Published: August 2020

Metabolic pathway inference from genomic sequence information is an integral scientific problem with wide ranging applications in the life sciences. As sequencing throughput increases, scalable and performative methods for pathway prediction at different levels of genome complexity and completion become compulsory. In this paper, we present reMap (relabelingmetabolic pathway data with groups) a simple, and yet, generic framework, that performs relabeling examples to a different set of labels, characterized as groups. A pathway group is comprised of a subset of statistically correlated pathways that can be further distributed between multiple pathway groups. This has important implications for pathway prediction, where a learning algorithm can revisit a pathway multiple times across groups to improve sensitivity. The relabeling process in reMap is achieved through an alternating feedback process. In the first feed-forward phase, a minimal subset of pathway groups is picked to label each example. In the second feed-backward phase, reMap’s internal parameters are updated to increase the accuracy of mapping examples to pathway groups. The resulting pathway group dataset is then be used to train a multi-label learning algorithm. reMap’s effectiveness was evaluated on metabolic pathway prediction where resulting performance metrics equaled or exceeded other prediction methods on organismal genomes with improved predictive performance.
MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions
Authors: Backx Elyne , Wauters Elke , Baldan Jonathan , Van Bulck Mathias , Michiels Ellis , Heremans Yves , De Paep Diedert Luc , Kurokawa Mineo , Goyama Susumu , Bouwens Luc , Jacquemin Patrick , Houbracken Isabelle , Rooman Ilse
Published: August 2020

Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell-specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed in mice since the availability of human cells is scarce.

Here, we applied a non-genetic lineage tracing method of human pancreatic exocrine acinar and duct cells that allowed cell-type-specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized.

RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in ‘Pathways of cancer’ with prominence ofMECOM (EVI-1), atranscription factor that was not expressed by duct cells. During mouse embryonic development, pre-acinar cells also transiently expressed MECOM and in the adult mouse pancreas, MECOM was re-expressed when mice were subjected to acute and chronic pancreatitis, conditions in which acinar cells dedifferentiate. In human cells and in mice, MECOM expression correlated with and was directly regulated by SOX9. Mouse acinar cells that, by genetic manipulation, lose the ability to upregulate MECOM showed impaired cell adhesion, more prominent acinar cell death and suppressed acinar cell dedifferentiation by limited ERK signaling.

In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.
Evolution of flowering time in a selfing annual plant: Roles of adaptation and genetic drift
Authors: Gay Laurène , Dhinaut Julien , Jullien Margaux , Vitalis Renaud , Navascués Miguel , Ranwez Vincent , Ronfort Joëlle
Published: August 2020

Resurrection studies are a useful tool to measure how phenotypic traits have changed in populations through time. If these traits modifications correlate with the environmental changes that occurred during the time period, it suggests that the phenotypic changes could be a response to selection. Selfing, through its reduction of effective size, could challenge the ability of a population to adapt to environmental changes. Here, we used a resurrection study to test for adaptation in a selfing population ofMedicago truncatula, by comparing the genetic composition and flowering times across 22 generations. We found evidence for evolution towards earlier flowering times by about two days and a peculiar genetic structure, typical of highly selfing populations, where some multilocus genotypes (MLGs) are persistent through time. We used the change in frequency of the MLGs through time as a multilocus fitness measure and built a selection gradient that suggests evolution towards earlier flowering times. Yet, a simulation model revealed that the observed change in flowering time could be explained by drift alone, provided the effective size of the population is small enough (<150). These analyses suffer from the difficulty to estimate the effective size in a highly selfing population, where effective recombination is severely reduced.
Females and hermaphrodites of the gynodioeciousGeranium maculatumrespond similarly to soil nutrient availability
Authors: Putney Katharine , Wolf Mavis , Mason Chase , Chang Shu-Mei
Published: August 2020

Sexual dimorphism in plant growth and/or reproductive responses to the surrounding environment has been documented in some plant species. In gynodioecious plants, it is especially important to understand whether females and hermaphrodites differ in their response to environmental stressors, as the fitness of females relative to hermaphrodites determines the extent to which these separate sexes are maintained in natural populations. Soil nutrient availability is of particular importance given the different nutrient requirements of male and female sexual functions in plants. Here, we evaluated and compared the growth of females and hermaphrodites ofGeranium maculatumin response to varying levels of nutrients. Using a greenhouse experiment, we manipulated the overall nutrient, nitrogen, and phosphorus levels in the soil and measured growth, allocation, and leaf quality responses in both females and hermaphrodites. We found that sexes responded similarly in their growth and allocation responses to nutrient availability, albeit evidence that female leaf chlorophyll content may have increased more than that of hermaphrodites across soil nitrogen levels. Our findings demonstrate that hermaphrodites differ from females in terms of their physiological response to varying nutrient levels, however these physiological differences did not translate into meaningful growth or reproduction differences.
5’XP sRNA-seq: Efficient Identification of Transcripts With and Without 5’ Phosphorylation Reveals Evolutionary Conserved Small RNA
Authors: Kugelberg Unn , Nätt Daniel , Skog Signe , Kutter Claudia , Öst Anita
Published: August 2020

Small RNA (sRNA) sequencing has been critical for our understanding of many cellular processes, including gene regulation. Nonetheless, the varying biochemical properties of sRNA, such as 5’ nucleotide modifications, makes many sRNA subspecies incompatible with common protocols for sRNA sequencing. Here we describe 5XP-seq that outlines a novel strategy that solves this problem. By tagging 5’P sRNA during library preparation, 5XP-seq combines an open approach that includes all types of 5’-terminal modifications (5’X), with a selective approach for 5-phosphorylated sRNA (5’P). We show that 5XP-seq not only enriches phosphorylated miRNA and piRNA but successfully discriminates these sRNA from all other sRNA species. We further demonstrate the importance of this strategy by successful inter-species validation of sRNAs that would have otherwise failed, including human to insect translation of several tRNA (tRFs) and rRNA (rRFs) fragments. By combining 5’ insensitive library strategies with 5’ sensitive tagging, we have solved an intrinsic bias in modern sRNA sequencing that will help us reveal the true complexity and the evolutionary significance of the sRNA world.
Inheritance of Rootstock Effects in Avocado (Persea americanaMill.) cv. Hass
Authors: Reyes-Herrera Paula H. , Muñoz-Baena Laura , Velásquez-Zapata Valeria , Patiño Laura , Delgado-Paz Oscar A. , Díaz-Diez Cipriano A. , Navas-Arboleda Alejandro A. , Cortés Andrés J.
Published: August 2020

Grafting is typically utilized to merge adapted seedling rootstocks with highly productive clonal scions. This process implies the interaction of multiple genomes to produce a unique tree phenotype. Yet, the interconnection of both genotypes obscures individual contributions to phenotypic variation (i.e. rootstock-mediated heritability), hampering tree breeding. Therefore, our goal was to quantify the inheritance of seedling rootstock effects on scion traits using avocado (Persea americanaMill.) cv. Hass as model fruit tree. We characterized 240 rootstocks from 8 avocado cv. Hass orchards in three regions of the province of Antioquia, in the northwest Andes of Colombia, using 13 microsatellite markers (simple sequence repeats – SSRs). Parallel to this, we recorded 20 phenotypic traits (including morphological, eco-physiological, and fruit yield and quality traits) in the scions for three years (2015–2017). Relatedness among rootstocks was inferred through the genetic markers and inputted in a ‘genetic prediction’ model in order to calculate narrow-sense heritabilities (h2) on scion traits. We used three different randomization tests to highlight traits with consistently significant heritability estimates. This strategy allowed us to capture five traits with significant heritability values that ranged from 0.33 to 0.45 and model fits (R2) that oscillated between 0.58 and 0.74 across orchards. The results showed significance in the rootstock effects for four complex harvest and quality traits (i.e. total number of fruits, number of fruits with exportation quality, and number of fruits discarded because of low weight or thrips damage), while the only morphological trait that had a significant heritability value was overall trunk height (an emergent property of the rootstock-scion interaction). These findings suggest the inheritance of rootstock effects, beyond root phenotype, on a surprisingly wide spectrum of scion traits in ‘Hass’ avocado. They also reinforce the utility of SSR markers for relatedness reconstruction and genetic prediction of complex traits. This research is, up to date, the most cohesive evidence of narrow-sense inheritance of rootstock effects in a tropical fruit tree crop. Ultimately, our work reinforces the importance of considering the rootstock-scion interaction to broaden the genetic basis of fruit tree breeding programs, while enhancing our understanding of the consequences of grafting.
Analysis of paralogs in target enrichment data pinpoints multiple ancient polyploidy events inAlchemillas.l. (Rosaceae)
Authors: Morales-Briones Diego F. , Gehrke Berit , Huang Chien-Hsun , Liston Aaron , Ma Hong , Marx Hannah E. , Tank David C. , Yang Ya
Published: August 2020

Target enrichment is becoming increasingly popular for phylogenomic studies. Although baits for enrichment are typically designed to target single-copy genes, paralogs are often recovered with increased sequencing depth, sometimes from a significant proportion of loci, especially in groups experiencing whole-genome duplication (WGD) events. Common approaches for processing paralogs in target enrichment datasets include random selection, manual pruning, and mainly, the removal of entire genes that show any evidence of paralogy. These approaches are prone to errors in orthology inference or removing large numbers of genes. By removing entire genes, valuable information that could be used to detect and place WGD events is discarded. Here we use an automated approach for orthology inference in a target enrichment dataset of 68 species ofAlchemillas.l. (Rosaceae), a widely distributed clade of plants primarily from temperate climate regions. Previous molecular phylogenetic studies and chromosome numbers both suggested ancient WGDs in the group. However, both the phylogenetic location and putative parental lineages of these WGD events remain unknown. By taking paralogs into consideration, we identified four nodes in the backbone ofAlchemillas.l. with an elevated proportion of gene duplication. Furthermore, using a gene-tree reconciliation approach we established the autopolyploid origin of the entireAlchemillas.l. and the nested allopolyploid origin of four major clades within the group. Here we showed the utility of automated tree-based orthology inference methods, previously designed for genomic or transcriptomic datasets, to study complex scenarios of polyploidy and reticulate evolution from target enrichment datasets.
BayesFactorFMRI: Implementing Bayesian second-level fMRI analysis with multiple comparison correction and Bayesian meta-analysis of fMRI images with multiprocessing
Authors: Han Hyemin
Published: August 2020

BayesFactorFMRI is a tool developed with R and Python to allow neuroimaging researchers to conduct Bayesian second-level analysis and Bayesian meta-analysis of fMRI image data with multiprocessing. This tool expedites computationally intensive Bayesian fMRI analysis through multiprocessing. Its GUI allows researchers who are not experts in computer programming to feasibly perform Bayesian fMRI analysis. BayesFactorFMRI is available via Zenodo and GitHub for download. It would be widely reused by neuroimaging researchers who intend to analyse their fMRI data with Bayesian analysis with better sensitivity compared with classical analysis while improving performance by distributing analysis tasks into multiple processors.
The N34S mutation of SPINK1 may impact the kinetics of trypsinogen activation to cause early trypsin release in the pancreas
Authors: Sun Zhuyezi , Kolossváry István , Kozakov Dima , Sahin-Tóth Miklós , Vajda Sandor
Published: August 2020

The N34S variant of the trypsin inhibitor SPINK1 is the clinically most significant risk factor for chronic pancreatitis, but the underlying molecular mechanism could not be identified. Molecular dynamics simulations and docking of the generated conformational ensemble of SPINK1 to trypsin show that the mutation reduces the fraction of conformations that can directly participate in productive association, thereby reducing the association rate. The small change is difficult to detect by measuring the kinetics of SPINK1 binding to trypsin. However, kinetic modeling reveals that even a small change in the inhibition rate affects the trypsinogen to trypsin conversion rate at the early stage of the reaction when the trypsin concentration is very low, and the impact is substantially amplified by the autocatalytic mechanism of the conversion. Thus, the slightly reduced inhibition rate shortens the delay in the activation of trypsin release, which is therefore occurs within the pancreas.
Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1
Authors: Zutz Ariane , Chen Lin , Sippl Franziska , Schölz Christian
Published: August 2020

During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established, which circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically undistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells.

Here, we employed a simple and convenient cell-based reporter system, which enables sample handling under biosafety level (BSL)-1 conditions, to screen for compounds that were able to reactivate latent HIV-1. The assay showed a high dynamic signal range and reproducibility with an average Z-factor of 0.77, classifying the system as robust. The assay was used for high-throughput screening (HTS) of an epigenetic compound library in combination with titration and cell-toxicity studies and revealed several potential new latency reversing agents (LRAs). Further validation in well-known latency model systems verified earlier studies and identified two novel compounds with very high reactivation efficiency and low toxicity. Both drugs, namely N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) and 2',3'-difluoro-[1,1'-biphenyl]-4-carboxylic acid, 2-butylhydrazide (SR-4370), showed comparable performances to other already known LRAs, did not activate CD4+T-cells or caused changes in the composition of PBMCs as shown by flow cytometry analyses.

Both compounds may represent an effective new treatment possibility for revocation of latency in HIV-1 infected individuals.
Potent anti-SARS-CoV-2 Antibody Responses are Associated with Better Prognosis in Hospital Inpatient COVID-19 Disease
Authors: Tighe Patrick J. , Urbanowicz Richard A. , Fairclough C. Lucy , McClure C. Patrick , Thomson Brian J. , Gomez Nancy , Chappell Joseph G. , Tsoleridis Theocharis , Loose Matthew , Carlile Matthew , Moore Christopher , Holmes Nadine , Sang Fei , Hrushikesh Divyateja , Clark Gemma , Temperton Nigel , Brooks Tim , Ball Jonathan K. , Irving William L. , Tarr Alexander W.
Published: August 2020

COVID-19 continues to cause a pandemic, having infected more than 20 million people globally. Successful elimination of the SARS-CoV-2 virus will require an effective vaccine. However, the immune correlates of infection are currently poorly understood. While neutralizing antibodies are believed to be essential for protection against infection, the contribution of the neutralizing antibody response to resolution of SARS-CoV-2 infection has not yet been defined. In this study the antibody responses to the SARS-CoV-2 spike protein and nucleocapsid proteins were investigated in a UK patient cohort, using optimised immunoassays and a retrovirus-based pseudotype entry assay. It was discovered that in severe COVID-19 infections an early antibody response to both antigens was associated with improved prognosis of infection. While not all SARS-CoV-2-reactive sera were found to possess neutralizing antibodies, neutralizing potency of sera was found to be greater in patients who went on to resolve infection, compared with those that died from COVID-19. Furthermore, viral genetic variation in spike protein was found to influence the production of neutralizing antibodies. Infection with the recently described spike protein variant 614G produced higher levels of neutralizing antibodies when compared to viruses possessing the 614D variant. These findings support the assertion that vaccines targeting generation of neutralizing antibodies may be useful at limiting SARS-CoV-2 infection. Assessment of the antibody responses to SARS-CoV-2 at time of diagnosis will be a useful addition to the diagnostic toolkit, enabling stratification of clinical intervention for severe COVID-19 disease.
A Single Chromosome Strain ofS. cerevisiaeExhibits Diminished Ethanol Metabolism and Tolerance
Authors: Doughty Tyler W. , Yu Rosemary , Chao Lucy Fang-I , Qin Zhongjun , Siewers Verena , Nielsen Jens
Published: August 2020

This study characterized the growth, metabolism, and transcriptional profile of aS. cerevisiaestrain with a single large chromosome that was constructed via successive chromosomal fusions. The single chromosome strain exhibited a longer lag phase, increased doubling time, and lower final biomass concentration compared with a wildtype strain when grown on YPD. These phenotypes were amplified when ethanol was added to the medium or used as the sole carbon source. RNAseq analysis showed diminished induction of genes involved in diauxic shift, ethanol metabolism, fatty-acid ß-oxidation, and methylglyoxal catabolism during growth on ethanol compared to the reference strain. Enzyme-constrained metabolic modeling predicted that decreased flux through these poorly induced enzymes results in diminished ATP formation and decreased biomass accumulation observed. Together, these observations suggest that switch-like control of carbon source dependent gene expression inS. cerevisiaerequires genome arrangement into multiple chromosomes.
Comprehensive genome sequencing analysis as a promising option in the prenatal diagnosis of fetal structural anomalies: a prospective study
Authors: Zhou Jia , Yang Ziying , Sun Jun , Liu Lipei , Zhou Xinyao , Liu Fengxia , Xing Ya , Cui Shuge , Xiong Shiyi , Liu Xiaoyu , Yang Yingjun , Wei Xiuxiu , Zou Gang , Wang Zhonghua , Wei Xing , Wang Yaoshen , Zhang Yun , Yan Saiying , Wu Fengyu , Zeng Fanwei , Duan Tao , Wang Jian , Yang Yaping , Peng Zhiyu , Sun Luming
Published: August 2020

Purpose

Genome sequencing (GS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are few. We aimed to evaluate the feasibility of GS as a first-line approach in prenatal diagnosis and compare its clinical value with the chromosomal microarray analysis (CMA) plus exome sequencing (ES) sequential testing.

Methods

We applied trio GS (∼40-fold) in parallel with CMA plus ES to investigate the genetic basis for structural or growth anomalies in 111 fetuses and compared their results.

Results

GS covered all genetic variants in 22 diagnosed cases detected by CMA plus ES, yielding a diagnostic rate of 19.8% (22/110). Moreover, GS provided more comprehensive and precise genetic information than CMA plus ES, revealing twin fetuses with an imbalanced translocation arising from a balanced paternal translocation and one fetus with an extra pathogenic variant in theGJA8gene, and incidentally identified intrauterine CMV infection in a growth-restricted fetus.

Conclusion

Compared with CMA plus ES, GS offers a more comprehensive view of the genetic etiology of fetal anomalies and provides clues for nongenetic factors such as intrauterine infection. Our study demonstrates the feasibility of GS as a promising first-line test in prenatal diagnosis.
Jaw Kinematics and Tongue Protraction-Retraction during Chewing and Drinking in the Pig
Authors: Olson Rachel A. , Montuelle Stéphane J. , Chadwell Brad A. , Curtis Hannah , Williams Susan H.
Published: August 2020

Mastication and drinking are rhythmic and cyclic oral behaviors that require interactions between the tongue, jaw, and a food or liquid bolus, respectively. During mastication, the tongue transports and positions the bolus for breakdown between the teeth. During drinking, the tongue aids in ingestion and then transports the bolus to the oropharynx. The objective of this study is to compare jaw and tongue kinematics during chewing and drinking in pigs. We hypothesize there will be differences in jaw gape cycle dynamics and tongue protraction-retraction between behaviors. Mastication cycles had an extended slow-close phase, reflecting tooth-food-tooth contact, whereas drinking cycles had an extended slow-open phase, corresponding to tongue protrusion into the liquid. Drinking jaw movements were of lower magnitude for all degrees of freedom examined (jaw protraction, yaw, and pitch), and were bilaterally symmetrical with virtually no yaw. The magnitude of tongue protraction-retraction (Tx) was greater during mastication than drinking, but there were minimal differences in the timing of maximum and minimum tongue Tx relative to the jaw gape cycle between behaviors. However, during drinking, the tongue tip is often located outside the oral cavity for the entire cycle, leading to differences in behaviors in the timing of anterior marker maximum tongue Tx. This demonstrates that there is variation in tongue-jaw coordination between behaviors. These results show that jaw and tongue movements vary significantly between mastication and drinking, which hint at differences in the central control of these behaviors.

Summary statement

Differences in the magnitude and timing of tongue and jaw movements and the anteroposterior positioning of the tongue during chewing and drinking demonstrate key differences in coordination of these behaviors.
Mutanofactin promotes bacterial adhesion and biofilm formation of cariogenicStreptococcus mutans
Authors: Li Zhong-Rui , Du Yongle , Sun Jin , Pan Aifei , Zeng Lin , Maboudian Roya , Burne Robert A. , Qian Pei-Yuan , Zhang Wenjun
Published: August 2020

CariogenicStreptococcus mutansis known as a predominant etiological agent of dental caries due to its exceptional capacity in forming biofilms. From strains ofS. mutansisolated from dental plaque, we here discover a polyketide/non-ribosomal peptide biosynthetic gene cluster,muf, which directly correlates with a strong biofilm-forming capability. We then identify themuf-associated bioactive product, mutanofactin-697 that contains a novel molecular scaffold, along with its biosynthetic logic. Further mode-of-action studies reveal mutanofactin-697 binds toS. mutanscells nonspecifically, increases bacterial hydrophobicity, and promotes bacterial adhesion and subsequent biofilm formation. Our findings provide the first example of a microbial secondary metabolite promoting biofilm formation via a physicochemical approach, highlighting the significance of secondary metabolism in mediating critical processes related to the development of dental caries.