bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversal of heavy metal-induced antibiotic resistance by dandelion root extracts and taraxasterol
Authors: Yang Kerry , Zhang Yanjie
Published: July 2020

Introduction. Metal exposure is an important factor for inducing antibiotic resistance in bacteria. Dandelion extracts have been used for centuries in traditional Chinese and Native American medicine.

Aim. We assessed the effects of dandelion water extracts and taraxasterol on heavy metal-induced antibiotic resistance in

Escherichia coli

as well as the underlying mechanisms.

Methodology. Dandelion extracts were obtained through 4 h of boiling in distilled water. Bacterial growth was monitored with a spectrophotometer. Biochemical assays were performed to assess the activities and gene transcriptions of β-lactamase and acetyltransferase. Oxidative stress was determined using an oxidation-sensitive probe, H2DCFDA.

Results. The present study demonstrated that higher concentrations of nickel (>5 µg ml−1), cadmium (>0.1 µg ml−1), arsenic (>0.1 µg ml−1) and copper (>5 µg ml−1) significantly inhibited the growth of

E. coli

. Lower concentrations of nickel (0.5 µg ml−1), cadmium (0.05 µg ml−1) and arsenic (0.05 µg ml−1) had no effect on bacterial growth, but helped the bacteria become resistant to two antibiotics, kanamycin and ampicillin. The addition of dandelion root extracts and taraxasterol significantly reversed the antibiotic resistance induced by these heavy metals. The supplements of antibiotics and cadmium generated synergistic effects on the activities of β-lactamase and acetyltransferase (two antibiotic resistance-related proteins), which were significantly blocked by either dandelion root extract or taraxasterol. In contrast, oxidative stress was not involved in the preventative roles of dandelion root extracts and taraxasterol in heavy metal-induced antibiotic resistance.

Conclusion. This study suggests that heavy metals induce bacterial antibiotic resistance and dandelion root extracts and taraxasterol could be used to help reverse bacterial resistance to antibiotics.
Airway expression of SARS-CoV-2 receptor, ACE2, and proteases, TMPRSS2 and furin, in severe asthma
Authors: Kermani Nazanin Zounemat , Song Woo-Jung , Lunt Alan , Badi Yusef , Versi Ali , Guo Yike , Sun Kai , Bhavsar Pank , Howarth Peter , Dahlen Sven-Erik , Sterk Peter J , Djukanovic Ratko , Adcock Ian M , Chung Kian Fan
Published: July 2020

Background

Patients with severe asthma may have a greater risk of dying from COVID-19 disease caused by SARS-CoV-2 virus. Angiotensin converting enzyme 2 (ACE2) receptor and enzyme proteases, transmembrane protease, serine 2 (TMPRSS2) and furin are needed for the attachment and invasion of the virus into host cells. We determined whether their expression in the airways of severe asthma patients is increased.

Method

We examined the microarray mRNA expression of ACE2, TMPRSS2 and furin in the sputum, bronchial brush and bronchial biopsies of participants in the European U-BIOPRED cohort.

Results

ACE2 and furin sputum gene expression was significantly increased in severe non-smoking asthma compared to mild-moderate asthma and healthy volunteers. By contrast, TMPRSS2 expression in bronchial biopsy and bronchial brushings was increased in severe smoking and ex-smoking asthmatics, and so was furin expression in bronchial brushings. Several clinical parameters including male gender, oral steroid use and nasal polyps were positively associated with ACE2, TMPRSS2 and furin expression levels. There was a higher expression of ACE2 and furin in the sputum neutrophilic molecular phenotype with inflammasome activation compared to the eosinophilic Type2-high or paucigranulocytic phenotypes. The enrichment score of the IL-13-Type2 gene signature was positively correlated with ACE2, TMPRSS2 and furin levels.

Conclusion

These key determinants of virus entry into the lungs may contribute to the poorer outcomes from COVID-19 disease in patients with severe asthma.

“take home” message

In severe asthma, gene expression of ACE, TMPRSS2 and furin are elevated compared to mild-moderate asthma and healthy volunteers, particularly in neutrophilic asthma. This might explain the increased risk of death in severe asthma afflicted with COVID19.
Factors Influencing 4th Year Medical Students’ Rank Lists of Radiology Residency Programs
Authors: Rios Florentino Saenz , Alwan Shadan , Nguyen Quan
Published: July 2020

Background

Applicants for radiology residency programs consider various factors when completing their ranking lists of programs. However, in making their decision, there is usually minimal objective data that can guide applicants in creating their rank list.

Purpose

The goal of the study is to determine which factors in order of importance lead to the decision to rank one residency program over the other.

Methods

This study was an anonymous, cross-sectional study conducted through an online survey. Emails were sent out to applicants who had interviewed at the University of Texas Medical Branch’s Diagnostic Radiology department the day after match day. The survey consisted of a single open-ended question asking the survey taker to list four factors in order of importance that guided their program rank list. Results were compiled, tallied, and categorized to find common themes between the applicant’s preferences.

Results

Of the 73 surveys sent out, a total of 30 applicants responded for a response rate of 41%. The most common “1st preference” factors were “Reputation,” “Location,” and “Work Environment,” with 23.33%, 20%, and 20% of applicants considering these the most important factors in ranking a program.

Conclusion

Despite reputation being the most common “1st preference” factor, “Work Environment” was more commonly mentioned overall, being mentioned in 23.35% of all answers compared to “Reputation” 12.5%. These results, combined with the difficulty in changing a program’s location and reputation, make it clear that programs should focus on building and highlighting a healthy work environment to attract applicants.
Red blood cell distribution width (RDW) in Hospitalized COVID-19 Patients
Authors: Ramachandran Preethi , Gajendran Mahesh , Perisetti Abhilash , Elkholy Karim Osama , Chakraborti Abhishek , Lippi Giuseppe , Goyal Hemant
Published: July 2020

Introduction

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing dramatic morbidity and mortality worldwide. The Red Blood Cell Distribution Width (RDW) has been strongly associated with increased morbidity and mortality in multiple diseases.

Objective

To assess if elevated RDW is associated with unfavorable outcomes in hospitalized COVID-19.

Methods

We retrospectively studied clinical outcomes of hospitalized COVID-19 patients for their RDW values. In-hospital mortality was defined as primary outcome, while septic shock, need for mechanical ventilation, and length of stay (LOS) were secondary outcomes.

Results

A total of 294 COVID-19 patients were finally studied. Overall prevalence of increased RDW was 49.7% (146/294). RDW was associated with increased risk of in-hospital mortality (aOR, 4.5; 95%CI, 1.4-14.3) and septic shock (aOR, 4.6; 95%CI, 1.4-15.1) after adjusting for anemia, ferritin, and lactate. The association remained unchanged even after adjusting for other clinical confounders such as age, sex, body mass index, coronary artery disease, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease. No association was found instead with mechanical ventilation and median LOS.

Conclusion

Elevated RDW in hospitalized COVID-19 patients is associated with a significantly increased risk of mortality and septic shock.
Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart
Authors: Cahill Thomas J. , Sun Xin , Ravaud Christophe , Villa del Campo Cristina , Klaourakis Konstantinos , Lupu Irina-Elena , Lord Allegra M. , Browne Cathy , Jacobsen Sten Eirik W. , Greaves David R. , Jackson David G. , Cowley Sally A. , James William , Choudhury Robin P. , Vieira Joaquim Miguel , Riley Paul R.
Published: July 2020

Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that resident macrophages in the subepicardial compartment of the developing heart coincide with the emergence of new lymphatics and interact closely with the nascent lymphatic capillaries. Consequently, global macrophage-deficiency led to extensive vessel disruption with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and fetal liver. Moreover,Csf1r+andCx3cr1+myeloid sub-lineages were found to play essential functions in the remodeling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was found to be required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.

Summary statement

Tissue-resident macrophages are indispensable mediators of lymphatic vessel formation during heart development and function to remodel the vascular plexus.
Population Pharmacokinetics of an Anti-PD-1 Antibody Camrelizumab in Patients with Multiple tumor types and model informed dosing strategy
Authors: Wang Chen-yu , Sheng Chang-cheng , Ma Guang-li , Xu Da , Liu Xiao-qin , Wang Yu-ya , Zhang Li , Cui Chuan-liang , Xu Bing-he , Song Yu-qin , Zhu Jun , Jiao Zheng
Published: July 2020

Objective

Camrelizumab, a programmed cell death 1 (PD-1) inhibitor, has been approved for the treatment of relapsed or refractory classical Hodgkin lymphoma. The aim of this study was to perform a population pharmacokinetics (PK) analysis of camrelizumab to quantify the impact of patient characteristics on PK and to investigate the appropriateness of flat dose in the dosing regimen.

Methods

A total of 3298 camrelizumab concentrations from 133 patients from four studies were analyzed using nonlinear mixed effects modeling. Covariate model building was conducted using stepwise forward addition and backward elimination. Monte Carlo simulation was conducted to compare exposures of 200 mg and 3 mg/kg every 2-week regimens.

Results

The PK of camrelizumab were adequately described by a two-compartment model with parallel linear and nonlinear clearances. Baseline albumin had significant effects on linear clearance, and weight had effects on inter-compartmental clearance. Moreover, 200 mg and 3 mg/kg regimens provide similar exposure distributions with no advantage to either dosing approach.

Conclusion

Population PK analysis provided an integrated evaluation of the impact of albumin and weight on the PK of camrelizumab. It also provided evidence that neither the flat-dose nor the weight-based dose regimen was advantageous over the other for most patients with tumors.
Functional characterization ofPolr3ahypomyelinating leukodystrophy mutations in theS. cerevisiaehomolog,RPC160
Authors: Moir Robyn D. , Lavados Christian , Lee JaeHoon , Willis Ian M.
Published: July 2020

Mutations in RNA polymerase III (Pol III) cause hypomeylinating leukodystrophy (HLD) and neurodegeneration in humans. POLR3A and POLR3B, the two largest Pol III subunits, together form the catalytic center and carry the majority of disease alleles. Disease-causing mutations include invariant and highly conserved residues that are predicted to negatively affect Pol III activity and decrease transcriptional output. A subset of HLD missense mutations in POLR3A cluster in the pore region that provides nucleotide access to the Pol III active site. These mutations were engineered at the corresponding positions in theSaccharomyces cerevisiaehomolog, Rpc160, to evaluate their functional deficits. None of the mutations caused a growth or transcription phenotype in yeast. Each mutation was combined with a frequently occurring pore mutation, POLR3A G672E, which was also wild-type for growth and transcription. The double mutants showed a spectrum of phenotypes from wild-type to lethal, with only the least fit combinations showing an effect on Pol III transcription. In one slow-growing temperature-sensitive mutant the steady-state level of tRNAs was unaffected, however global tRNA synthesis was compromised, as was the synthesis ofRPR1andSNR52RNAs. Affinity-purified mutant Pol III was broadly defective in both factor-independent and factor-dependent transcriptionin vitroacross genes that represent the yeast Pol III transcriptome. Thus, the robustness of yeast to Pol III leukodystrophy mutations inRPC160can be overcome by a combinatorial strategy.
Environment-conditioned male fertility of HD-ZIP IV transcription factor mutantocl4: impact on 21-nt phasiRNA accumulation in pre-meiotic maize anthers
Authors: Yadava Pranjal , Tamim Saleh , Zhang Han , Teng Chong , Zhou Xue , Meyers Blake C. , Walbot Virginia
Published: July 2020

Environment-conditioned genic male sterility is a key strategy used to produce hybrid seeds efficiently in many crops, with the exception of maize. The underlying molecular mechanisms of environment-conditioned sterility are poorly understood. Here, we report a derivative line of the male sterileouter cell layer 4(ocl4) mutant of maize, in which fertility was restored and perpetuated over several generations, under warm growing conditions. Conditionally fertileocl4anthers exhibit the anatomical abnormality of a partially duplicated endothecial layer, just like their sterile counterparts. We profiled the dynamics of phased, small interfering RNAs (phasiRNAs) during pre-meiotic development in fully sterile and various grades of semi-fertileocl4anthers. We found that the biogenesis of 21-nt phasiRNAs is largely dependent onOcl4at three key steps: (1) production ofPHASprecursor transcripts, (2) expression of miR2118 that modulates precursor processing, and (3) accumulation of 21-nt phasiRNAs. We propose that 21-nt reproductive phasiRNAs buffer development under unfavorable environmental conditions and are dispensable under favorable conditions.
Ecological effects of stress drive bacterial evolvability under sub-inhibitory antibiotic treatments
Authors: Vasse Marie , Bonhoeffer Sebastian , Frenoy Antoine
Published: July 2020

1

Stress is thought to increase mutation rate and thus to accelerate evolution. In the context of antibiotic resistance, sub-inhibitory treatments could then lead to enhanced evolvability, thereby fueling the adaptation of pathogens. Conducting a meta-analysis of published experimental data as well as our own experiments, we found that the increase in mutation rates triggered by antibiotic treatments is often canceled out by reduced population size, resulting in no overall increase in genetic diversity. A careful analysis of the effect of ecological factors on genetic diversity revealed that the potential for regrowth during recovery phase after treatment plays a crucial role in evolvability and is the main predictor of increased genetic diversity in experimental data.
An Opportune and Relevant Design for Studying the Health Trajectories of Healthcare Workers
Authors: Ebinger Joseph E. , Botwin Gregory J. , Albert Christine M. , Berg Anders H. , Binek Aleksandra , Botting Patrick , Brystrom Cory , Chavira Cindy , Figueiredo Jane C. , Ghandi Soniya S. , Goldzweig Caroline Lubick , Hasan Wohaib , Henglin Mir , Huballa Khalil , Hussain Shehnaz K. , Jain Mohit , Jenrette John E. , Joung Sandy , Kim Elizabeth H. , McArdle Angela , Miller Shaun J. , Minissian Margo , Nguyen Trevor Trung , Chazarin Blandine , Raedschelders Koen , Rashid Mohamad A. , Riggs Richard V. , Sobhani Kimia , Sun Nancy , Tourtellotte Warren G. , McGovern Dermot P. B. , Braun Jonathan G. , Van Eyk Jennifer E. , Cheng Susan , Miles Peggy B.
Published: July 2020

We describe the rationale, design, and implementation of baseline enrollment for a longitudinal, observational cohort study of healthcare workers. The importance of workplace as a characteristic of interest in population-based studies has become increasingly apparent over time. Most adults spend a majority of their waking hours living in their workplace environment, which serves as a source of unique as well as shared exposures, stressors, and related determinants of health. A rapidly expanding segment of the working population includes those individuals who work in the fields of healthcare. The healthcare workforce, at large, represents an increasingly diverse subset of the population with broad exposures; some exposures are specific to the workplace and others are common to persons living in the community. Importantly, healthcare workers tend to have general interest and willingness to participate in research, in addition to stable employment and easy access to on-site clinical research assessment locations. Accordingly, from a population of individuals working at a large medical delivery network, we enrolled over 6300 healthcare workers into a cohort study involving survey data collection on medical history, work environment, and family and living situation; this information was linked to participant electronic health record data and collected biospecimens.
Indication for SARS-CoV-2 serology: first month follow-up
Authors: Coste Alix T. , Jaton Katia , Papadimitriou-Olivgeris Matthaios , Croxatto Antony , Greub Gilbert
Published: July 2020

SARS-CoV-2 detection is mainly performed by RT-PCR but recently serological tests were made available. A first one month follow-up of the SARS-CoV-2 serology records was performed in our laboratory to precise the diversity and proportion of the SARS-CoV-2 serology test indications and to identify new valid indications (meningoencephalitis, vasculitis, …)
Chopping the tail: how preventing superspreading can help to maintain COVID-19 control
Authors: Kain Morgan P. , Childs Marissa L. , Becker Alexander D. , Mordecai Erin A.
Published: July 2020

Disease transmission is notoriously heterogeneous, and SARS-CoV-2 is no exception. A skewed distribution where few individuals or events are responsible for the majority of transmission can result in explosive, superspreading events, which produce rapid and volatile epidemic dynamics, especially early or late in epidemics. Anticipating and preventing superspreading events can produce large reductions in overall transmission rates. Here, we present a compartmental (SEIR) epidemiological model framework for estimating transmission parameters from multiple imperfectly observed data streams, including reported cases, deaths, and mobile phone-based mobility that incorporates individual-level heterogeneity in transmission using previous estimates for SARS-CoV-1 and SARS-CoV-2. We parameterize the model for COVID-19 epidemic dynamics by estimating a time-varying transmission rate that incorporates the impact of non-pharmaceutical intervention strategies that change over time, in five epidemiologically distinct settings—Los Angeles and Santa Clara Counties, California; Seattle (King County), Washington; Atlanta (Dekalb and Fulton Counties), Georgia; and Miami (Miami-Dade County), Florida. We find the effective reproduction number ℛE dropped below 1 rapidly following social distancing orders in mid-March, 2020 and remained there into June in Santa Clara County and Seattle, but climbed above 1 in late May in Los Angeles, Miami, and Atlanta, and has trended upward in all locations since April. With the fitted model, we ask: how does truncating the tail of the individual-level transmission rate distribution affect epidemic dynamics and control? We find interventions that truncate the transmission rate distribution while partially relaxing social distancing are broadly effective, with impacts on epidemic growth on par with the strongest population-wide social distancing observed in April, 2020. Given that social distancing interventions will be needed to maintain epidemic control until a vaccine becomes widely available, “chopping off the tail” to reduce the probability of superspreading events presents a promising option to alleviate the need for extreme general social distancing.
Rapid detection of SARS-CoV-2 infection by multicapillary column coupled ion mobility spectrometry (MCC-IMS) of breath. A proof of concept study
Authors: Steppert Claus , Steppert Isabel , Sterlacci William , Bollinger Thomas
Published: July 2020

There is an urgent need for screening of patients having a communicable viral disease to cut infection chains.

We could recently demonstrate that MCC-IMS of breath is able to identify Influenza-A infected patients. With decreasing Influenza epidemic and upcoming SARS-CoV-2 infections we went on and also analysed patients with suspected SARS-CoV-2 infections.

75 patients, 34m, 41f, aged 64.4 ± 15.4 years, 14 positive for Influenza-A, 16 positive for SARS-CoV-2, the remaining 44 patients were used as controls. In one patient RT-PCR was highly suspicious of SARS-CoV-2 but initially inconclusive.

Besides RT-PCR analysis of nasopharyngeal swabs all patients underwent MCC-IMS analysis of breath. There was no difference in gender or age according to the groups.

97.3% of the patients could be correctly classified to the respective group by discriminant analysis. Even the inconclusive patient could be mapped to the SARS-CoV-2 group applying the discrimination function.

Conclusion

MCC-IMS is able to detect SARS-CoV-2 infection and Influenza-A infection in breath. As this method provides exact, fast non-invasive diagnosis it should be further developed for screening of communicable viral diseases.

Trial registration: ClinicalTrial.gov, NCT04282135 Registered 20 February 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04282135?term=IMS&draw=2&rank=1
Disruption of the renal service during COVID-19 pandemic, physicians survey responses from 5 countries
Authors: Abdelaziz Tarek Samy , Elsayed Eman , Fatthy Moataz
Published: July 2020

The outbreak of COVID-19 has significant impact on health care systems. The workflow in renal care facilities and dialysis facilities is complex. The aim of his study was to explore multinational renal physician perspective about the disruption of outflow of renal service amid COVID-19 pandemic.

Methods

we distributed a questionnaire electronically to renal physicians of various grades from 5 countries. The questionnaire was formulated of 9 questions with domains centered on the acute and chronic renal services

Results

97 physicians took part in the survey from 5 countries. 58% of the participating renal physicians agreed that there has been disruption to the acute service offered to renal patients. 38% of the physicians who took the survey report disruption to the hemodialysis facilities.

Conclusion

At this challenging time of the pandemic, it is important to perform audits and quality control to explore the deficiencies of acute and chronic renal care pathways.
Is an integrated model of school eye health delivery more cost effective than a vertical model? An implementation research in Zanzibar
Authors: Chan Ving Fai , Omar Fatma , Yard Elodie , Mashayo Eden , Mulewa Damaris , Drake Lesley , Wepo Mary , Minto Hasan
Published: July 2020

Objective

To review and compare the cost effectiveness of the integrated model (IM) and vertical model (VM) of school eye health programme in Zanzibar.

Methods and Analysis

This 6-month implementation research was conducted in four districts in Zanzibar. Nine and ten schools were recruited into the IM and VM respectively. In the VM, teachers conducted eye health screening and education only while these eye health components were added to the existing School Feeding Programme (IM). The number of children screened and identified was collected monthly. A review of project accounts records was conducted with 19 key informants. The actual costs were calculated for each cost categories, and costs per child screened and cost per child identified were compared between the two models.

Results

Screening coverage was 96% and 90% in the IM and VM with 297 children (69.5%) from the IM and 130 children (30.5%) from VM failed eye health screening. The 6-month eye health screening cost for VM and IM was USD 6 728 and USD 7 355. The cost per child screened for IM and VM were USD 1.23 and USD 1.31, and the cost per child identified were USD 51.75 and USD 24.76 respectively.

Conclusions

Both models achieved high coverage of eye health screening with the IM being a more cost-effective school eye health delivery screening compared to VM with great opportunities for cost savings.

Key messages

There is a dearth of information on the actual cost of school eye health (SEH) delivery. This was the first implementation research to review and compare cost effectiveness of the integrated model (IM) versus the vertical model (VM) SEH delivery in Africa.

VM used 1.2 times more resources per child screened compared to the IM and the cost per child identified in the VM is twice that of the IM, thus the IM is highly cost effective.

Stakeholders in low- and middle-income settings will be better able to plan for a cost-effective SEH delivery model that suits their contexts and needs using these findings.
Structural and functional characterization of allatostatin receptor type-C ofThaumetopoea pityocamparevealed the importance of Q2716.55residue in G protein-dependent activation pathway
Authors: Shahraki Aida , Isbilir Ali , Dogan Berna , Lohse Martin J. , Durdagi Serdar , Birgul-Iyison Necla
Published: July 2020

Insect neuropeptide receptors are among the potential targets for designing next-generation pesticides. Activation of allatostatin receptor type C (AstR-C), a G Protein-coupled receptor (GPCR), upon stimulation with its endogenous ligand, allatostatin C (AST-C), leads to the inhibition of juvenile hormone (JH) secretion that consequently regulates physiology of insects. Here we conductedin silicoandin vitroapproaches to characterize the structure and function of AstR-C ofThaumetopoea pityocampa (T.pit), a well-known pest in Mediterranean countries. The sequence of AstR-C and AST-C were derived from whole genome sequencing (WGS) data. Resonance energy transfer (RET) methods were used to investigate the downstream effectors of the receptor and the temporal kinetics of G protein activation. Three-dimensional (3D) structure of AstR-C constructed via homology modeling methods was subjected to molecular dynamics (MD) simulations and docking studies to identify the orthosteric pocket. Our results showed thatT.pitAstR-C couples to Gαi/o subtype of G proteins at sub-nanomolar ranges of the the ligand with the G protein recruitment and activation kinetics of ∼4 and 6 seconds, respectively, when 1 nM AST-C is administered. At the increasing concentration of native ligand, βarrestin was shown to be recruited at nanomolar ranges the ligand. Docking and MD simulation studies revealed the importance of extracellular loop 2 (ECL2) inT.pitAstRC/AST-C interaction, and combination ofin silicoandin vitromethods supported the accuracy of the built model and the predicted orthosteric pocket. Q2716.55(Ballesteros-Weinstein generic numbering) was found to have a substantial role in G protein dependent activation of AstR-C possibly via contributing to the flexibility of the structure.
Interactomic affinity profiling by holdup assay: acetylation and distal residues impact the PDZome-binding specificity of PTEN phosphatase
Authors: Jané Pau , Gógl Gergő , Kostmann Camille , Bich Goran , Girault Virginie , Caillet-Saguy Célia , Eberling Pascal , Vincentelli Renaud , Wolff Nicolas , Travé Gilles , Nominé Yves
Published: July 2020

Protein domains often recognize short linear protein motifs composed of a core conserved consensus sequence surrounded by less critical, modulatory positions. Here we used an accurate experimental approach combining high-throughput holdup chromatographic assay and fluorescence polarization to measure quantitative binding affinity profiles of the PDZ domain-binding motif (PBM) of PTEN phosphatase towards the 266 known human PDZ domains. Inclusion of N-terminal flanking residues, acetylation or mutation of a lysine at a modulatory position significantly altered the PDZome-binding profile of the PTEN PBM. A specificity index is also introduced to quantify the specificity of a given PBM over the complete PDZome. Our results highlight the impact of modulatory residues and post-translational modifications on PBM interactomes and their specificity.
S-acylation is involved in tonoplast targeting of flax resistance protein M
Authors: Batistič Oliver
Published: July 2020

Several plant resistance proteins require accurate targeting to cellular membranes for effective pathogen defence function. The resistance protein variant M fromLinum ussitatissimum(flax) protects plants against the flax rust disease and is specifically targeted to the vacuolar membrane. This localization mechanism involves the S-acylation of cysteine residues within the N-terminus of the protein. Moreover, the M S-acylation and targeting signal likely binds to membranes in the absence of lipid modifications and can switch from the vacuolar membrane to the plasma membrane depending on the S-acylation status. Importantly, plasma membrane targeting was observed when the short targeting signal from M was expressed in anArabidopsis thalianapat10 mutant plant. On the other hand, tonoplast localization of the N-terminal S-acylation domain was reconstituted in the mutant plant upon co-expression of two highly related PAT10 enzymes from flax. In contrast to the Golgi and tonoplast targetedArabidopsisPAT10, the two homologous enzymes from flax mainly localized to the plasma membrane and were partially observed at the vacuolar membrane when expressed in flax as well as inArabidopsiscells. This implicates that S-acylation of flax proteins could occur at the plasma membrane and that the lipid modification is required for subsequent routing to the vacuolar membrane, which could be also involved in the localization mechanism of M.
A multi-network comparative analysis of transcriptome and translatome in cardiac remodeling
Authors: Boileau Etienne , Doroudgar Shirin , Riechert Eva , Jürgensen Lonny , Ho Thanh Cao , Katus Hugo A , Völkers Mirko , Dieterich Christoph
Published: July 2020

Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered gene networks in early cardiac remodeling. Using co-expression analysis, we reveal how sub-networks are orchestrated into functional modules associated with pathological phenotypes. We show how transcriptome networks are only partially reproducible at the translatome level. We find unappreciated hub genes and genes in the transcriptional network that were rewired in the translational network, and associated with semantically different subsets of enriched functional terms, providing novel insights into the complexity of the organization ofin vivocardiac regulatory networks.
Network-based protein-protein interaction prediction method maps perturbations of cancer interactome
Authors: Qiu Jiajun , Chen Kui , Zhong Chunlong , Zhu Sihao , Ma Xiao
Published: July 2020

The perturbations of protein-protein interactions (PPIs) were found to be the main cause of cancer. Previous gene relationship prediction methods which were trained with non-disease gene interaction data were not compatible to map the PPI network in cancer. Therefore, we established a novel cancer specific PPI prediction method dubbed NECARE, which was based on relational graph convolutional network (R-GCN) with knowledge-based features. It achieved the best performance with a Matthews correlation coefficient (MCC) = 0.84±0.03 and an F1 = 91±2% comparing with other methods. With NECARE, we mapped the cancer interactome atlas and revealed that the perturbations of PPIs were enriched on 1362 genes, which were named cancer hub genes. Those genes were found to over-represent with mutations occurring at protein-macromolecules binding interfaces. Furthermore, over 42% of cancer treatment-related genes belonged to hub genes, which were significantly related to the prognosis of 32 types of cancers. Finally, by coimmunoprecipitation, we confirmed that the NECARE prediction method was highly reliable with a 90% accuracy. Overall, we provided the novel network-based protein-protein interaction prediction method and mapped the perturbation of cancer interactome. NECARE is available at:https://github.com/JiajunQiu/NECARE.
Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction
Authors: Mayr Fabian , Möller Gabriele , Garscha Ulrike , Fischer Jana , Castaño Patricia Rodríguez , Inderbinen Silvia G. , Temml Veronika , Waltenberger Birgit , Schwaiger Stefan , Hartmann Rolf W. , Gege Christian , Martens Stefan , Odermatt Alex , Pandey Amit V. , Werz Oliver , Adamski Jerzy , Stuppner Hermann , Schuster Daniela
Published: July 2020

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature’s treasures, however, could be used more effectively. Yet, reliable pipelines for large scale target prediction of natural products are still rare. We have developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs) – a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target prediction and guidance on using the respective tools.
Is there a neuropathic-like component to endometriosis-associated pain? Results from a large cohort questionnaire study
Authors: Coxon Lydia , Wiech Katja , Vincent Katy
Published: July 2020

Background

Pain is one of the primary symptoms of endometriosis, a chronic inflammatory condition characterised by the presence of endometrial tissue outside the uterus. Endometriosis-associated pain is commonly considered as nociceptive in nature but its clinical presentation suggests that it might have neuropathic-like properties in a subgroup of patients.

Methods

This is a cross sectional study using an online survey. The survey was distributed by patient support websites. The survey was composed of validated questionnaires assessing pain symptoms, psychological measures and questions about number of surgeries.

Main results and the role of chance

We had 1417 responses which met the inclusion criteria. Using standard painDETECT cut-off scores, we found that pain was classified as neuropathic in 40% of patients and as mixed neuropathic/nociceptive in a further 35%. In line with observations in other neuropathic conditions, the neuropathic subgroup reported higher pain intensities, greater psychological distress and cognitive impairment. Neuropathic pain was also more likely in those with more surgeries to the abdomen and a longer history of pain. As revealed by a cluster analysis, those with a neuropathic pain component could further be divided into two subgroups based on their sensory profile.

Conclusions

The data presented here indicate that endometriosis-associated pain includes a neuropathic-like component in a substantial proportion of women. Although further investigation is required, our finding challenges the current conceptualisation of endometriosis-associated pain as nociceptive and advocates for a new perspective on this type of pain, which is so debilitating to a large number of women.
Additive and non-additive epigenetic signatures of hybridisation between fish species with different mating systems
Authors: Berbel-Filho Waldir M. , Tatarenkov Andrey , Pacheco George , Espírito-Santo Helder M. V. , Lira Mateus G. , de Leaniz Carlos Garcia , Avise John C. , Lima Sergio M. Q. , Rodríguez-López Carlos M. , Consuegra Sofia
Published: July 2020

Hybridisation is a major source of evolutionary innovation. However, several prezygotic and postzygotic factors influence its likelihood and evolutionary outcomes. Differences in mating systems can have a major effect on the extent and direction of hybridisation and introgression. In plants, epigenetic mechanisms help to stabilize hybrid genomes and contribute to reproductive isolation, but the relationship between genetic and epigenetic changes in animal hybrids is unclear. We analysed the extent of a unique case of natural hybridisation between two genetically distant mangrove killifish species with different mating systems,Kryptolebias hermaphroditus(self-fertilising) andK. ocellatus(outcrossing), and the methylation patterns of their hybrids. Hybridisation rate between the species ranged between 14% and 26%. Although co-existing parental species displayed highly distinct genetic (microsatellites and SNPs) and methylation patterns (37,000 differentially methylated cytosines), our results indicate that F1 hybrids are viable and able to backcross with parental species. Hybrids had predominantly intermediate methylation patterns (88.5% of the sites) suggesting additive effects, as expected from hybridisation between genetically distant species. Differentially methylated cytosines between hybrids and both parental species (5,800) suggest that introgressive hybridisation may play a role in generating novel genetic and epigenetic variation which could lead to species diversification. We also found a small percentage of non-additive epigenetic effects which might act as an evolutionary bet-hedging strategy and increase fitness under environmental change.
A chronic photocapacitor implant for noninvasive neurostimulation with deep red light
Authors: Silverå-Ejneby Malin , Jakešová Marie , Ferrero Jose J. , Migliaccio Ludovico , Zhao Zifang , Berggren Magnus , Khodagholy Dion , Đerek Vedran , Gelinas Jennifer , Głowacki Eric Daniel
Published: July 2020

Implantable clinical neuroelectronic devices are limited by a lack of reliable, safe, and minimally invasive methods to wirelessly modulate neural tissue. Here, we address this challenge by using organic electrolytic photocapacitors (OEPCs) to perform chronic peripheral nerve stimulation via transduction of tissue-penetrating deep-red light into electrical signals. The operating principle of the OEPC relies on efficient charge generation by nanoscale organic semiconductors comprising nontoxic commercial pigments. OEPCs integrated on an ultrathin cuff are implanted, and light impulses at wavelengths in the tissue transparency window are used to stimulate from outside of the body. Typical stimulation parameters involve irradiation with pulses of 50-1000 μs length (638 or 660 nm), capable of actuating the implant about 10 mm below the skin. We detail how to benchmark performance parameters of OEPCs firstex vivo, andin vivousing a rat sciatic nerve. Incorporation of a microfabricated zip-tie mechanism enabled stable, long-term nerve implantation of OEPC devices in rats, with sustained ability to non-invasively mediate neurostimulation over 100 days. OEPC devices introduce a high performance, ultralow volume (0.1 mm3), biocompatible approach to wireless neuromodulation, with potential applicability to an array of clinical bioelectronics.
Consolidated bioprocessing of corn cob-derived hemicellulose: engineered industrialSaccharomyces cerevisiaeas efficient whole cell biocatalysts
Authors: Cunha Joana T. , Romaní Aloia , Inokuma Kentaro , Johansson Björn , Hasunuma Tomohisa , Kondo Akihiko , Domingues Lucília
Published: July 2020

Consolidated bioprocessing, which combines saccharolytic and fermentative abilities in a single microorganism, is receiving increased attention to decrease environmental and economic costs in lignocellulosic biorefineries. Nevertheless, the economic viability of lignocellulosic ethanol is also dependent of an efficient utilization of the hemicellulosic fraction, which is mainly composed of xylose and may comprise up to 40 % of the total biomass. This major bottleneck is mainly due to the necessity of chemical/enzymatic treatments to hydrolyze hemicellulose into fermentable sugars and to the fact that xylose is not readily consumed bySaccharomyces cerevisiae– the most used organism for large-scale ethanol production. In this work, industrialS. cerevisiaestrains, presenting robust traits such as thermotolerance and improved resistance to inhibitors, were evaluated as hosts for the cell-surface display of hemicellulolytic enzymes and optimized xylose assimilation, aiming at the development of whole-cell biocatalysts for consolidated bioprocessing of corn cob-derived hemicellulose. These modifications allowed the direct production of ethanol from non-detoxified hemicellulosic liquor obtained by hydrothermal pretreatment of corn cob, reaching an ethanol titer of 11.1 g/L corresponding to a yield of 0.328 gram per gram of potential xylose and glucose, without the need for external hydrolytic catalysts. Also, consolidated bioprocessing of pretreated corn cob was found to be more efficient for hemicellulosic ethanol production than simultaneous saccharification and fermentation with addition of commercial hemicellulases. These results show the potential of industrialS. cerevisiaestrains for the design of whole-cell biocatalysts and paves the way for the development of more efficient consolidated bioprocesses for lignocellulosic biomass valorization, further decreasing environmental and economic costs.
Chromosome-scale assembly of the coral endosymbiontSymbiodinium microadriaticumgenome provides insight into the unique biology of dinoflagellate chromosomes
Authors: Nand Ankita , Zhan Ye , Salazar Octavio R. , Aranda Manuel , Voolstra Christian R. , Dekker Job
Published: July 2020

Dinoflagellates are major primary producers in the world’s oceans, the cause of harmful algal blooms, and endosymbionts of marine invertebrates. Much remains to be understood about their biology including their peculiar crystalline chromosomes. Here we used Hi-C to order short read-based sub-scaffolds into 94 chromosome-scale scaffolds of the genome of the coral endosymbiontSymbiodinium microadriaticum. Hi-C data show that chromosomes are folded as linear rods within which loci separated by up to several Mb are highly packed. Each chromosome is composed of a series of structural domains separated by boundaries. Genes are enriched towards the ends of chromosomes and are arranged in unidirectional blocks that alternate between top and bottom strands. Strikingly, the boundaries of chromosomal domains are positioned at sites where transcription of two gene blocks converges, indicating a correlation between gene orientation, transcription and chromosome folding. Some chromosomes are enriched for genes involved in specific biological processes (e.g., photosynthesis, and nitrogen-cycling), and functionally related genes tend to co-occur at adjacent sites in the genome. All chromosomes contain several repeated segments that are enriched in mobile elements. The assembly of theS. microadriaticumgenome and initial description of its genetic and spatial organization provide a foundation for deeper exploration of the extraordinary biology of dinoflagellates and their chromosomes.
Arctic charr phenotypic responses to abrupt temperature change: an insight into how cold water fish could respond to extreme climatic events
Authors: Hooker Oliver E. , Adams Colin E. , Chavarie Louise
Published: July 2020

Phenotypic plasticity, the ability of an organism to express multiple phenotypes in response to the prevailing environmental conditions without genetic change, may occur as a response to anthropogenic environmental change. Arguably, the most significant future anthropogenic environment change is contemporary climate change. Given that increasing climate variability is predicted to pose a greater risk than directional climate change, we tested the effect of a water temperature differential of 4 ºC on the Arctic charr phenotypic response within a generation. We demonstrate that Arctic charr phenotype can respond rapidly and markedly to an environmental cue. The plastic response to different temperature regimes comprised a shift in the mean phenotype coupled with a reduction in the between-individual phenotypic variation in the expressed head shape. The magnitude of shape difference was cumulative over time but the rate of divergence diminished as fish became larger. Individuals raised in the elevated temperature treatment expressed a phenotype analogous to a benthivorous ecotype of this species rather than that of the parental pelagic feeding form. The response of cold-water freshwater species to temperature change is likely to be an interaction between the capacity of the organism for phenotypic plasticity, the speed of mean change in the environment (e.g., temperature), and the degree of short interval variation in the environment.
DiffNets: deep learning the structural determinants of proteins biochemical properties by comparing different structural ensembles
Authors: Ward Michael D. , Zimmerman Maxwell I. , Meller Artur , Chung Moses , Swamidass S.J. , Bowman Gregory R.
Published: July 2020

Understanding the structural determinants of a protein’s biochemical properties, such as activity and stability, is a major challenge in biology and medicine. Comparing computer simulations of protein variants with different biochemical properties is an increasingly powerful means to drive progress. However, success often hinges on dimensionality reduction algorithms for simplifying the complex ensemble of structures each variant adopts. Unfortunately, common algorithms rely on potentially misleading assumptions about what structural features are important, such as emphasizing larger geometric changes over smaller ones. Here we present DiffNets, self-supervised autoencoders that avoid such assumptions, and automatically identify the relevant features, by requiring that the low-dimensional representations they learn are sufficient to predict the biochemical differences between protein variants. For example, DiffNets automatically identify subtle structural signatures that predict the relative stabilities of β-lactamase variants and duty ratios of myosin isoforms. DiffNets should also be applicable to understanding other perturbations, such as ligand binding.
Gut cancer increases the risk forDrosophilato be preyed upon by hunting spiders
Authors: Duneau David , Buchon Nicolas
Published: July 2020

Predators are thought to prey on individuals that are in poor physical condition, although the evidence supporting this is ambiguous. We tested if sick individuals where more predated usingDrosophila melanogasterflies as manipulable preys. We asked whether hunting spiders, trapped from the wild, would selectively prey upon flies with compromised health (i.e. chronically infected or cancerous) versus healthy flies under laboratory conditions. Flies chronically infected with the bacteriumProvidencia rettgeri, a naturalDrosophilapathogen, were not selectively preyed upon by jumping spiders. We strengthened and confirmed our finding with another hunting spider species, small wolf spiders. We discuss that this result supports the hypothesis that chronic infection is associated with reduced symptoms notably to avoid the potentially deadly consequences of host predation on pathogens. We then induced colon cancer in some of the flies and asked whether the presence of cancer led to selective predation; there is little evidence for this, even in vertebrates. As the cancer developed, the incidence of predation by jumping spiders on the afflicted flies increased. We conclude that disease can have different lethal consequences through predation, even in invertebrate species, and that cancer is a factor in selective predation. Our results may explain why early tumours, but not metastasized cancers, are commonly detected in organisms in the wild, as cancer bearing individuals are rapidly eliminated due to the strong selective pressure against them.