bluuebunny/crossref_metadata_2025 huggingface dataset:
PLAZA 5.0: extending the scope and power of comparative and functional genomics in plants
Authors: Van Bel Michiel , Silvestri Francesca , Weitz Eric M , Kreft Lukasz , Botzki Alexander , Coppens Frederik , Vandepoele Klaas
Published: October 2021

PLAZA is a platform for comparative, evolutionary, and functional plant genomics. It makes a broad set of genomes, data types and analysis tools available to researchers through a user-friendly website, an API, and bulk downloads. In this latest release of the PLAZA platform, we are integrating a record number of 134 high-quality plant genomes, split up over two instances: PLAZA Dicots 5.0 and PLAZA Monocots 5.0. This number of genomes corresponds with a massive expansion in the number of available species when compared to PLAZA 4.0, which offered access to 71 species, a 89% overall increase. The PLAZA 5.0 release contains information for 5 882 730 genes, and offers pre-computed gene families and phylogenetic trees for 5 274 684 protein-coding genes. This latest release also comes with a set of new and updated features: a new BED import functionality for the workbench, improved interactive visualizations for functional enrichments and genome-wide mapping of gene sets, and a fully redesigned and extended API. Taken together, this new version offers extended support for plant biologists working on different families within the green plant lineage and provides an efficient and versatile toolbox for plant genomics. All PLAZA releases are accessible from the portal website: https://bioinformatics.psb.ugent.be/plaza/.
ViRBase v3.0: a virus and host ncRNA-associated interaction repository with increased coverage and annotation
Authors: Cheng Jun , Lin Yunqing , Xu Linfu , Chen Kechen , Li Qi , Xu Kaixin , Ning Lin , Kang Juanjuan , Cui Tianyu , Huang Yan , Zhao Xiaoyang , Wang Dong , Li Yanhui , Su Xi , Yang Bin
Published: October 2021

As a means to aid in the investigation of viral infection mechanisms and identification of more effective antivirus targets, the availability of a source which continually collects and updates information on the virus and host ncRNA-associated interaction resources is essential. Here, we update the ViRBase database to version 3.0 (http://www.virbase.org/ or http://www.rna-society.org/virbase/). This update represents a major revision: (i) the total number of interaction entries is now greater than 820,000, an approximately 70-fold increment, involving 116 virus and 36 host organisms, (ii) it supplements and provides more details on RNA annotations (including RNA editing, RNA localization and RNA modification), ncRNA SNP and ncRNA-drug related information and (iii) it provides two additional tools for predicting binding sites (IntaRNA and PRIdictor), a visual plug-in to display interactions and a website which is optimized for more practical and user-friendly operation. Overall, ViRBase v3.0 provides a more comprehensive resource for virus and host ncRNA-associated interactions enabling researchers a more effective means for investigation of viral infections.
Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence
Authors: Ghadaouia Sabrina , Olivier Marc-Alexandre , Martinez Aurélie , Kientega Tibila , Qin Jian , Lambert-Lanteigne Patrick , Cardin Guillaume B , Autexier Chantal , Malaquin Nicolas , Rodier Francis
Published: October 2021

Loss of telomeric DNA leads to telomere uncapping, which triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Here, we show that in normal cells telomere uncapping triggers a focal telomeric DNA damage response accompanied by a transient cell cycle arrest. Subsequent cell division with dysfunctional telomeres resulted in sporadic telomeric sister chromatid fusions that gave rise to next-mitosis genome instability, including non-telomeric DNA lesions responsible for a stable, p53-mediated, senescence-associated proliferation arrest. Unexpectedly, the blocking of Rad51/RPA-mediated homologous recombination, but not non-homologous end joining (NHEJ), prevented senescence despite multiple dysfunctional telomeres. When cells approached natural replicative senescence, interphase senescent cells displayed genome instability, whereas near-senescent cells that underwent mitosis despite the presence of uncapped telomeres did not. This suggests that these near-senescent cells had not yet acquired irreversible telomeric fusions. We propose a new model for telomere-initiated senescence where tolerance of telomere uncapping eventually results in irreversible non-telomeric DNA lesions leading to stable senescence. Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability.
Reciprocal Effects Between Depressive Symptoms and Pain in Veterans over 50 Years of Age or Older
Authors: Griffin Sarah C , Young Jonathan R , Naylor Jennifer C , Allen Kelli D , Beckham Jean C , Calhoun Patrick S
Published: October 2021

Objective

Depression and chronic pain are major problems in American veterans, yet there is limited long-term research examining how they relate to one another in this population. This study examined the relationship between depressive symptoms and pain in U.S. veterans 50 years of age or older.

Methods

This study used data on veterans from the 2002–2016 waves of the Health and Retirement Study (n = 4,302), a large-scale observational study of Americans 50 years of age or older. Measures included a short form of the Center for Epidemiologic Studies Depression scale and two items assessing the presence and degree of pain. Analyses included random-intercept cross-lagged panel models (RI-CLPM).

Results

In the RI-CLPM, there were roughly equivalent cross-lagged effects between depressive symptoms and pain. There was also evidence that depressive symptoms and pain have a trait-like component and that these trait-like characteristics are associated.

Conclusions

These findings indicate that depressive symptoms and pain in veterans are stable characteristics in American veterans 50 years of age or older. There appear to be reciprocal effects between the two, whereby deviations in one’s typical depressive symptoms predict subsequent deviations in one’s pain level and vice versa; however, the size of these effects is very small. These findings suggest that clinicians should treat both depressive symptoms and pain, rather than assume that treatment benefits in one domain will lead to major benefits in another.
Bearing a Disproportionate Burden: Racial/Ethnic Disparities in Experiences of U.S.-Based Social Workers during the COVID-19 Pandemic
Authors: Ross Abigail M , Cederbaum Julie A , de Saxe Zerden Lisa , Zelnick Jennifer R , Ruth Betty J , Guan Ting
Published: October 2021

While social workers have served as frontline workers responding to the needs of vulnerable populations during COVID-19 pandemic, little is known about how social work professionals themselves have been impacted. This article explored the impact of COVID-19 on social work professionals’ mental health, physical health, and access to personal protective equipment (PPE). This was a cross-sectional web-based survey of social workers practicing in the United States (N = 3,118); data on demographic and workplace characteristics, physical and mental health, and safety concerns were collected between June and August of 2020. Univariate statistics were used to characterize the sample. Ordinal logistic and multinomial regression were used to achieve the research aims. The majority of participants reported either moderate or severe concerns related to mental (55 percent) and physical (55 percent) health; 36 percent of respondents indicated concerns about PPE access. Respondents’ concerns differed by demographic (e.g., race, age) and workplace characteristics (e.g., setting, role, region). Social workers of color are experiencing COVID-19-related concerns of significantly greater severity relative to their White counterparts. Findings highlight an immediate need to deepen understanding of the factors that contribute to these trends and identify mechanisms to support the frontline social work workforce most impacted.
Development of a Screening Tool for Pediatric Neuropathic Pain and Complex Regional Pain Syndrome
Authors: Mesaroli Giulia , Campbell Fiona , Hundert Amos , Birnie Kathryn A. , Sun Naiyi , Davidge Kristen M. , Lalloo Chitra , Davies-Chalmers Cleo , Harris Lauren , Stinson Jennifer
Published: October 2021

Objective:

Neuropathic pain (NP) and complex regional pain syndrome (CRPS) in children can result in significant disability and emotional distress. Early assessment and treatment could potentially improve pain, function, quality of life, and reduce costs to the health care system. Currently, there are no screening tools for pediatric NP and CRPS. This research aimed to develop and establish the content validity of a screening tool for pediatric NP and CRPS using a phased approach.

Materials and Methods:

Phase I surveyed clinical experts using a modified Delphi procedure to elicit disease concepts for inclusion. In phase II, a consensus conference including clinicians, researchers, and people with lived experience, informed the initial item pool. Consensus for item inclusion was achieved using a nominal group technique for voting. Phase III used iterative rounds of cognitive interviews with children aged 8 to 18 years with CRPS or NP to evaluate the tool’s comprehensiveness and individual item relevance and comprehensibility. Descriptive statistics were used to describe participant characteristics. Content analysis was used to analyze patient interviews.

Results:

Phase I (n=50) generated an initial item pool (22 items). Phase II generated a comprehensive item pool (50 items), after which an initial version of the screening tool was drafted. Following phase III (n=26) after item revision and elimination, 37 items remained.

Discussion:

The Pediatric PainSCAN is a novel screening tool that has undergone rigorous development and content validity testing. Further research is needed to conduct item reduction, determine scoring, and test additional measurement properties.
Neighborhood Socioeconomic Disadvantage and Disability After Critical Illness*
Authors: Falvey Jason R. , Murphy Terrence E. , Leo-Summers Linda , Gill Thomas M. , Ferrante Lauren E.
Published: October 2021

OBJECTIVES:

Factors common to socioeconomically disadvantaged neighborhoods, such as low availability of transportation, may limit access to restorative care services for critical illness survivors. Our primary objective was to evaluate whether neighborhood socioeconomic disadvantage was associated with an increased disability burden after critical illness. Our secondary objective was to determine if the effect differed for those discharged to the community compared with those discharged to a facility.

DESIGN:

Longitudinal cohort study with linked Medicare claims data.

SETTING:

United States.

PATIENTS:

One hundred ninety-nine older adults, contributing to 239 ICU admissions, who underwent monthly assessments of disability for 12 months following hospital discharge in 13 different functional tasks from 1998 to 2017.

MEASUREMENTS AND MAIN RESULTS:

Neighborhood disadvantage was assessed using the area deprivation index, a 1–100 ranking evaluating poverty, housing, and employment metrics. Those living in disadvantaged neighborhoods (top quartile of scores) were less likely to self-identify as non-Hispanic White compared with those in more advantaged neighborhoods. In adjusted models, older adults living in disadvantaged neighborhoods had a 9% higher disability burden over the 12 months following ICU discharge compared with those in more advantaged areas (rate ratio, 1.09; 95% Bayesian credible interval, 1.02–1.16). In the secondary analysis adjusting for discharge destination, neighborhood disadvantage was associated with a 14% increase in disability burden over 12 months of follow-up (rate ratio, 1.14; 95% credible interval, 1.07–1.21). Disability burden was 10% higher for those living in disadvantaged neighborhoods and discharged home as compared with those discharged to a facility, but this difference was not statistically significant (interaction rate ratio, 1.10; 95% credible interval, 0.98–1.25).

CONCLUSIONS:

Neighborhood socioeconomic disadvantage is associated with a higher disability burden in the 12 months after a critical illness. Future studies should evaluate barriers to functional recovery for ICU survivors living in disadvantaged neighborhoods.
Swell-induced flexural vibrations of a thickening ice shelf over a shoaling seabed
Authors: Meylan Michael H. , Ilyas Muhammad , Lamichhane Bishnu P. , Bennetts Luke G.
Published: October 2021

A solution method is developed for a linear model of ice shelf flexural vibrations in response to ocean waves, in which the ice shelf thickness and seabed beneath the ice shelf vary over distance, and the ice shelf/sub–ice-shelf cavity are connected to the open ocean. The method combines a decomposition of the ice shelf displacement profile at a prescribed frequency of motion into mode shapes of free vibrations, a finite-element method for the cavity water motion and a non-local operator to connect to the open ocean. An investigation is conducted into the effects of ice shelf thickening, seabed shoaling and the grounding-line conditions on time-harmonic ice shelf vibrations, induced by regular incident waves in the swell regime. Furthermore, results are given for ice shelf vibrations in response to irregular incident waves by superposing time-harmonic responses, and ocean-to-ice-shelf transfer functions are derived. The findings add to evidence that ice shelves experience appreciable flexural vibrations in response to swell, and that ice shelf thickening and seabed shoaling can have a considerable influence on predictions of how ice shelves respond to ocean waves.
A model for the spread of infectious diseases compatible with case data
Authors: Huang Norden E. , Qiao Fangli , Wang Qian , Qian Hong , Tung Ka-Kit
Published: October 2021

For epidemics such as COVID-19, with a significant population having asymptomatic, untested infection, model predictions are often not compatible with data reported only for the cases confirmed by laboratory tests. Additionally, most compartmental models have instantaneous recovery from infection, contrary to observation. Tuning such models with observed data to obtain the unknown infection rate is an ill-posed problem. Here, we derive from the first principle an epidemiological model with delay between the newly infected (
N
) and recovered (
R
) populations. To overcome the challenge of incompatibility between model and case data, we solve for the ratios of the observed quantities and show that log(
N
(
t
)/
R
(
t
)) should follow a straight line. This simple prediction tool is accurate in hindcasts verified using data for China and Italy. In traditional epidemiology, an epidemic wanes when much of the population is infected so that ‘herd immunity’ is achieved. For a highly contagious and deadly disease, herd immunity is not a feasible goal without human intervention or vaccines. Even before the availability of vaccines, the epidemic was suppressed with social measures in China and South Korea with much less than 5% of the population infected. Effects of social behaviour should be and are incorporated in our model.
Beneficial cumulative effects of old parental age on offspring fitness
Authors: Travers Laura M. , Carlsson Hanne , Lind Martin I. , Maklakov Alexei A.
Published: October 2021

Old parental age is commonly associated with negative effects on offspring life-history traits. Such parental senescence effects are predicted to have a cumulative detrimental effect over successive generations. However, old parents may benefit from producing higher quality offspring when these compete for seasonal resources. Thus, old parents may choose to increase investment in their offspring, thereby producing fewer but larger and more competitive progeny. We show that
Caenorhabditis elegans
hermaphrodites increase parental investment with advancing age, resulting in fitter offspring who reach their reproductive peak earlier. Remarkably, these effects increased over six successive generations of breeding from old parents and were subsequently reversed following a single generation of breeding from a young parent. Our findings support the hypothesis that offspring of old parents receive more resources and convert them into increasingly faster life histories. These results contradict the theory that old parents transfer a cumulative detrimental ‘ageing factor’ to their offspring.
IGenomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes
Authors: Cohen Ana SA , Farrow Emily G , Abdelmoity Ahmed T , Alaimo Joseph T , Amudhavalli Shivarajan M , Anderson John T , Bansal Lalit , Bartik Lauren , Baybayan Primo , Belden Bradley , Berrios Courtney D , Biswell Rebecca L , Buczkowicz Pawel , Buske Orion , Chakraborty Shreyasee , Cheung Warren A , Coffman Keith A , Cooper Ashley M , Cross Laura A , Curran Thomas , Dang Thuy Tien T , Elfrink Mary M , Engleman Kendra L , Fecske Erin D , Fieser Cynthia , Fitzgerald Keely , Fleming Emily A , Gadea Randi N , Gannon Jennifer L , Gelineau-Morel Rose N , Gibson Margaret , Goldstein Jeffrey , Grundberg Elin , Halpin Kelsee , Harvey Brian S , Heese Bryce A , Hein Wendy , Herd Suzanne M , Hughes Susan S , Ilyas Mohammed , Jacobson Jill , Jenkins Janda L , Jiang Shao , Johnston Jeffrey J , Keeler Kathryn , Korlach Jonas , Kussmann Jennifer , Lambert Christine , Lawson Caitlin , Le Pichon Jean-Baptiste , Leeder Steve , Little Vicki C , Louiselle Daniel A , Lypka Michael , McDonald Brittany D , Miller Neil , Modrcin Ann , Nair Annapoorna , Neal Shelby H , Oermann Christopher M , Pacicca Donna M , Pawar Kailash , Posey Nyshele L , Price Nigel , Puckett Laura MB , Quezada Julio F , Raje Nikita , Rowell William J , Rush Eric T , Sampath Venkatesh , Saunders Carol J , Schwager Caitlin , Schwend Richard M , Shaffer Elizabeth , Smail Craig , Soden Sarah , Strenk Meghan E , Sullivan Bonnie R , Sweeney Brooke R , Tam-Williams Jade B , Walter Adam M , Welsh Holly , Wenger Aaron M , Willig Laurel K , Yan Yun , Younger Scott T , Zhou Dihong , Zion Tricia N , Thiffault Isabelle , Pastinen Tomi
Published: October 2021

PURPOSE

To provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.

METHODS

Extensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).

RESULTS

Diagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naïve patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).

CONCLUSION

Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.
Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter
Authors: Iskarpatyoti Jason A , Shi Jianling , Rathor Abhay P S , Miao Yuxuan , Abraham Soman N
Published: October 2021

Mast cells (MCs) are highly granulated tissue resident hematopoietic cells and because of their capacity to degranulate and release many proinflammatory mediators, they are major effectors of chronic inflammatory disorders including asthma and urticaria. As MCs have the unique capacity to reform their granules following degranulationin vitro,their potential to undergo multiple cycles of degranulation and regranulationin vivohas been linked to their pathogenesis. However, it is not known what factors regulate MC regranulation let alone if MC regranulation occursin vivo. Here, we report that IgE-sensitized mice can undergo multiple bouts of regranulation, following repeated anaphylactic reactions. mTORC1, a critical nutrient sensor that activates protein and lipid synthesis, was found necessary for MC regranulation. mTORC1 activity in MCs was regulated by a glucose-6-phosphate transporter, Slc37a2, which was found to be necessary for increased glucose-6-phosphate and ATP levels during regranulation, two upstream signals of mTOR. Slc37a2 is highly expressed at the cell periphery early during regranulation where it appears to colocalize with mTORC1. Additionally, this transporter was found to concentrate extracellular metabolites within endosomes which are trafficked directly into nascent granules. Thus, the metabolic switch associated with MC regranulation is mediated by the interactions of a cellular metabolic sensor and a transporter of extracellular metabolites into MC granules.
Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for Covid-19 patients in A Real-Life Setting: A Single Institute Analysis
Authors: Kakinoki Yasutaka , Yamada Kazuki , Tanino Yoko , Suzuki Keiko , Ichikawa Takaya , Suzuki Naoki , Asari Go , Nakamura Ai , Kukita Shin , Uehara Akito , Saito Seisuke , Kuroda Shohei , Sakagami Hidemitsu , Nagashima Yuuki , Takahashi Kae , Suzuki Satoshi
Published: October 2021

Background

Recent data from clinical trial suggest that antibody cocktail therapy, a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to rapidly reduce the viral load and markedly decrease the risk of hospitalization or death among high-risk patients with coronavirus disease 2019 (Covid-19). However, it remains unclear how effective in a real-life clinical setting the therapy is.

Methods

We retrospectively analyzed mild to moderate Covid-19 patients with one or more high-risk factors for severe disease who consecutively underwent the antibody cocktail therapy of the disease in our institute in June 2021 through early September 2021, compared to those with high-risk factors who were isolated in non-medical facilities consecutively during the same period, thereby being not given the antibody cocktail therapy there. The key outcome was the percentage of patients with Covid-19-related deterioration which needed additional medical interventions, such as oxygen support or other antiviral therapies.

Results

Data from 55 patients with initially receiving antibody cocktail therapy and 53 patients with isolation into non-medical facilities are analyzed. 22 (41.5 %) of 53 patients with isolation facilities were finally hospitalized to receive medical interventions. On the other hand, 13 (23.6 %) of 55 patients with antibody cocktail therapy in our hospital subsequently underwent further medical interventions because of the progression. In multivariate analysis with variables of age, BMI, and high-risk factors, the antibody cocktail therapy significantly reduced 70 % in the need for further medical interventions compared to the initial isolation in the non-medical facilities (odds ratio=0.30, 95%CI [0.10-0.87], p=0.027). Furthermore, patients with 96% or above of SPO2 were significantly more favorable for the therapy than those with 95% or below of SPO2.

Conclusion

The treatment of antibody cocktail was closely linked to reduction in the need for further medical interventions. The result indicates that the antibody cocktail therapy is associated with reducing the strain on hospitals, which is related to the improvement of medical management for public health care in Covid-19 pandemic era.
Current surgical practice for children born with a cleft lip and/or palate in the United Kingdom
Authors: Fell Matthew , Davies Alex , Davies Amy , Chummun Shaheel , Cobb Alistair R.M. , Moar Kanwalraj , Wren Yvonne
Published: October 2021

Background

This study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate in the United Kingdom.

Methods

Data were obtained from the Cleft Collective, a national longitudinal cohort study. Data forms completed at the time of surgery included details on timing, technique and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.

Results

Between 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bi-modal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (p<0.001) and a 5–7day post-operative regime used more commonly for soft palatoplasties (p<0.001). Peri-operative steroids were used more commonly in palatoplasties than cheiloplasties (p<0.001) but tranexamic acid use was equivalent (p=0.73).

Conclusion

This study contributes to our understanding of current cleft surgical pathways in the United Kingdom and will provide a baseline for analysis of the effectiveness of utilised protocols.
New markers for qPCR detection of the dinoflagellate Alexandrium catenella in Chile
Authors: Espinoza Javiera , Yarimizu Kyoko , Nagai Satoshi , Espinoza-González Oscar , Guzman Leonardo , Fuenzalida Gonzalo
Published: October 2021

Alexandrium catenella (Whedon & Kofoid) is a dinoflagellate known as a primary source of paralytic shellfish poisoning in Chile. The distribution range of harmful algal blooms generated by this species has extended during the last decades, and the frequency of these events has increased. In this work, we developed TaqMan markers from Chilean strains that can be used to identify and quantify through qPCR, which can be implemented in monitoring programs for the early detection of this species.
Investigating the growth of an engineered strain of Cyanobacteria with an Agent-Based Model and a Recurrent Neural Network
Authors: Sakkos Jonathan , Weaver Joe , Robertson Connor , Li Bowen , Taniguchi Denis , Maheshwari Ketan , Ducat Daniel , Zuliani Paolo , McGough Andrew Stephen , Curtis Tom , Fuentes-Cabrera Miguel
Published: October 2021

A computational framework combining Agent-Based Models (ABMs) and Deep Learning techniques was developed to help design microbial communities that convert light and CO2 into useful bioproducts. An ABM that accounts for CO2, light, sucrose export rate and cell-to-cell mechanical interactions was used to investigate the growth of an engineered sucrose-exporting strain of Synechococcus elongatus PCC 7942. The ABM simulations produced population curves and synthetic images of colony growth. The curves and the images were analyzed, and growth was correlated to nutrients availability and colonies’ initial spatial distribution. To speed up the ABM simulations, a metamodel based on a Recurrent Neural Network, RNN, was trained on the synthetic images of growth. This metamodel successfully reproduced the population curves and the images of growth at a lower computational cost. The computational framework presented here paves the road towards designing microbial communities containing sucrose-exporting Synechococcus elongatus PCC 7942 by exploring the solution space in silico first.
A theoretical framework for proteome-scale single-molecule protein identification using multi-affinity protein binding reagents
Authors: Egertson Jarrett D. , DiPasquo Dan , Killeen Alana , Lobanov Vadim , Patel Sujal , Mallick Parag
Published: October 2021

The proteome is perhaps the most dynamic and valuable source of functional biological insight. Current proteomic techniques are limited in their sensitivity and throughput. A typical single experiment measures no more than 8% of the human proteome from blood or 35% from cells and tissues 1, 2. Here, we introduce a theoretical framework for a fundamentally different approach to proteomics that we call Protein Identification by Short-epitope Mapping (PrISM). PrISM utilizes multi-affinity reagents to target short linear epitopes with both a high affinity and low specificity. PrISM further employs a novel protein decoding algorithm that considers the stochasticity expected for single-molecule binding. In simulations, PrISM is able to identify more than 98% of proteins across the proteomes of a wide range of organisms. PrISM is robust to potential experimental confounders including false negative detection events and noise. Simulations of the approach with a chip containing 10 billion protein molecules show a dynamic range of 11.5 and 9.5 orders of magnitude for blood plasma and HeLa cells, respectively. If implemented experimentally, PrISM stands to rapidly quantify over 90% of the human proteome in a single experiment, potentially revolutionizing proteomics research.
Superresolution microscopy reveals partial preassembly and subsequent bending of the clathrin coat during endocytosis
Authors: Mund Markus , Tschanz Aline , Wu Yu-Le , Frey Felix , Mehl Johanna L. , Kaksonen Marko , Avinoam Ori , Schwarz Ulrich S. , Ries Jonas
Published: October 2021

Eukaryotic cells use clathrin-mediated endocytosis to take up a large range of extracellular cargos. During endocytosis, a clathrin coat forms on the plasma membrane, but it remains controversial when and how it is remodeled into a spherical vesicle.

Here, we use 3D superresolution microscopy to determine the precise geometry of the clathrin coat at large numbers of endocytic sites. Through pseudo-temporal sorting, we determine the average trajectory of clathrin remodeling during endocytosis. We find that clathrin coats assemble first on flat membranes to 50% of the coat area, before they become rapidly and continuously bent, and confirm this mechanism in three cell lines. We introduce the cooperative curvature model, which is based on positive feedback for curvature generation. It accurately describes the measured shapes and dynamics of the clathrin coat and could represent a general mechanism for clathrin coat remodeling on the plasma membrane.
Localization of the putative recombinase Pf-int to the apicoplast of Plasmodium falciparum
Authors: Berglar A. V. , Vembar S. S. , Gopaul D. N.
Published: October 2021

Diseases caused by apicomplexan parasites, such as malaria and toxoplasmosis cause ∼200 million (worldwide) and 1 million (Europe) infections, respectively, every year. Apicomplexa possess a non-photosynthetic organelle homologous to the plant chloroplast, the so-called apicoplast, that is essential for their growth and survival. This study focused on the Int recombinase, the first protein discovered in Plasmodium spp. with the features of a site-specific recombinase, and which has an apicoplast targeting leader sequence at its amino-terminus. Int is conserved amongst several apicomplexan parasites. In the human toxoplasmosis parasite, Toxoplasma, Int localizes to the apicoplast and Pf-Int, the P. falciparum member, belongs to the group of non-mutable essential genes in P. falciparum. A conserved protein that has been shown to be essential at least in one species and that localizes to an essential organelle may become a novel drug target. Therefore, the aim of this study was to confirm the sub-cellular localization of Int in the human malaria parasite P. falciparum. Using western blot analysis and immunofluorescence microscopy of P. falciparum asexual blood stages, we observed that Int partially co-localized with the apicoplast (to discrete foci adjacent to the nucleus).
New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27
Authors: Machushynets Nataliia , Elsayed Somayah S. , Du Chao , Siegler Maxime A. , de la Cruz Mercedes , Genilloud Olga , Hankemeier Thomas , van Wezel Gilles P.
Published: October 2021

Streptomycetes are major producers of bioactive natural products, including the majority of the antibiotics. While much if the low-hanging fruit has been discovered, it is predited that less than 5% of the chemical space has been mined. Here, we describe the novel actinomycins L1 and L2, which are produced by Streptomyces sp. MBT27. The molecules were discovered via metabolic analysis combined with molecular networking of cultures grown with different combinations of carbon sources. Actinomycins L1 and L2 are diastereoisomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via a unique spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Feeding anthranilamide to cultures of Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27 but only produces actinomycin X2, resulted in the production of actinomycin L. This shows that actinomycin L results from joining two distinct metabolic pathways, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram- positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.

IMPORTANCE

Actinomycin was the first antibiotic discovered in an actinobacterium by Selman Waksman and colleagues, as early as 1940. This period essentially marks the start of the ‘golden era’ of antibiotic discovery. Over time, emerging antimicrobial resistance (AMR) and the declining success rate of antibiotic discovery resulted in the current antibiotic crisis. We surprisingly discovered that under some growth conditions, Streptomyces sp. MBT27 can produce actinomycins that are significantly different from those that have been published so far. The impact of this work is not only that we have discovered a novel molecule with very interesting chemical modifications in one of the oldest antibiotics ever described, but also that this requires the combined action of primary and secondary metabolic pathways, namely the biosynthesis of anthranilamide and of actinomycin X2, respectively. The implication of the discovery is that even the most well-studied families of natural products may still have surprises in store for us.
SLX4 dampens MutSα-dependent mismatch repair
Authors: Guervilly Jean-Hugues , Blin Marion , Laureti Luisa , Baudelet Emilie , Audebert Stéphane , Gaillard Pierre-Henri
Published: October 2021

The tumour suppressor SLX4 plays multiple roles in the maintenance of genome stability, acting as a scaffold for structure-specific endonucleases and other DNA repair proteins. It directly interacts with the mismatch repair (MMR) protein MSH2 but the significance of this interaction remained unknown until recent findings showing that MutSβ (MSH2-MSH3) stimulates in vitro the SLX4-dependent Holliday junction resolvase activity. Here, we characterize the mode of interaction between SLX4 and MSH2, which relies on an MSH2-interacting peptide (SHIP box) that drives interaction of SLX4 with both MutSβ and MutSα (MSH2-MSH6). While we show that this MSH2 binding domain is dispensable for the well-established role of SLX4 in interstrand crosslink repair, we find that it mediates inhibition of MutSα-dependent MMR by SLX4, unravelling an unanticipated function of SLX4.
Altered Cardiolipin Metabolism is Associated with Cardiac Mitochondrial Dysfunction in Pulmonary Vascular Remodeled Perinatal Rat Pups
Authors: Cole Laura K. , Sparagna Genevieve C. , Dolinsky Vernon W. , Hatch Grant M.
Published: October 2021

Background

Pulmonary vascular remodeling (PVR)in uteroresults in the development of heart failure (HF). The alterations that occur in cardiac lipid and mitochondrial bioenergetics during the development ofin uteroPVR was unknown.

Methods

PVR was induced in pupsin uteroby exposure of pregnant dams to indomethacin and hypoxia. Cardiac lipids, echocardiographic function and cardiomyocyte mitochondrial function were subsequently examined.

Results

Perinatal rat pups with PVR exhibited elevated left and right cardiac ventricular internal dimensions and reduced ejection fraction and fractional shortening compared to controls. Cardiac myocytes from these pups exhibited increased glycolytic capacity and glycolytic reserve compared to controls. However, respiration with glucose as substrate was unaltered. Fatty acid oxidation and ATP-insensitive respiration were increased in isolated cardiac myocytes from these pups compared to controls indicating mitochondrial dysfunction. Although abundance of mitochondrial respiratory complexes were unaltered, increased trilinoleoyl-lysocardiolipin levels in these pups was observed. A compensatory increase in both cardiolipin (CL) and phosphatidylethanolamine (PE) content were observed due to increased synthesis of these phospholipids.

Conclusion

Alterations in cardiac cardiolipin and phospholipid metabolism in PVR rat pups is associated with the mitochondrial bioenergetic and cardiac functional defects observed in their hearts.

Impact statement

- Phospholipid metabolism was examined in pulmonary vascular remodeling in perinatal rat pups.

- Pulmonary vascular remodeling was inducedin uteroby treating pregnant dams with hypoxia and indomethacin at 19-21 days of gestation.

- The offspring exhibited altered pulmonary arterial remodeling with subsequent cardiac hypertrophy, ventricular dysfunction, cardiac myocyte mitochondrial dysfunction with altered fatty acid utilization.

- In addition, the offspring exhibited elevated cardiolipin, lysocardiolipin and phosphatidylethanolamine content which may potentially contribute to the cardiac mitochondrial dysfunction.
Dietary Proanthocyanidins Exert Localized Immunomodulatory Effects in Porcine Pulmonary and Gastrointestinal Tissues duringAscaris suum-induced Type 2 inflammation
Authors: Andersen-Civil Audrey Inge Schytz , Myhill Laura J. , Gökgöz Nilay Büdeyri , Engström Marica T. , Mejer Helena , Zeller Wayne E. , Salminen Juha-Pekka , Krych Lukasz , Lauridsen Charlotte , Nielsen Dennis S. , Thamsborg Stig M. , Williams Andrew R.
Published: October 2021

Bioactive dietary components may considerably influence intestinal health and resistance to enteric disease. Proanthocyanidins (PAC) are dietary polyphenols with putative health-promoting activity that have been increasingly studied for their anti-inflammatory and immunomodulatory effects. However, whether dietary PAC can regulate type-2 immune function and inflammation at mucosal surfaces remains unclear. Here, we investigated whether diets supplemented with purified PAC modulated pulmonary and intestinal mucosal immune responses during infection with the helminth parasiteAscaris suumin pigs.A. suuminfection induced a type 2-biased immune response in lung and intestinal tissues, characterized by pulmonary granulocytosis, increased Th2/Th1 T cell ratios in tracheal-bronchial lymph nodes, intestinal eosinophilia, and modulation of genes involved in mucosal barrier function and immunity. We observed that PAC had only minor effects on pulmonary immune responses, regardless of concurrentA. suuminfection. However, RNA-sequencing of intestinal tissues revealed that dietary PAC significantly enhanced transcriptional responses related to immune function, antioxidant responses, and cellular stress activity, both in uninfected andA. suum-infected animals.A. suuminfection and dietary PAC both induced distinct changes in gut microbiota composition, primarily in the jejunum and colon, respectively. Notably, PAC substantially increasedLimosilactobacillus reuteriabundance in the colon of both naïve andA. suum-infected animals. Thus, dietary PAC may have distinct beneficial effects on intestinal health during infection with mucosal pathogens, whilst having limited activity to modulate naturally-induced type-2 pulmonary inflammation. Our results shed further light on the mechanisms underlying the health-promoting properties of PAC-rich foods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.
Recording of cellular physiological histories along optically readable self-assembling protein chains
Authors: Linghu Changyang , An Bobae , Shpokayte Monika , Celiker Orhan T. , Shmoel Nava , Zhang Chi , Park Won Min , Ramirez Steve , Boyden Edward S.
Published: October 2021

Observing cellular physiological histories is key to understanding normal and disease-related processes, but longitudinal imaging is laborious and equipment-intensive. A tantalizing possibility is that cells could record such histories in the form of digital biological information within themselves, for later high-throughput readout. Here we show that this concept can be realized through information storage in the form of growing protein chains made out of multiple self-assembling subunits bearing different labels, each corresponding to a different cellular state or function, so that the physiological history of the cell can be visually read out along the chain of proteins. Conveniently, such protein chains are fully genetically encoded, and easily readable with simple, conventional optical microscopy techniques, compatible with visualization of cellular shape and molecular content. We use such expression recording islands (XRIs) to record gene expression timecourse downstream of pharmacological and physiological stimuli, in cultured neurons and in living mouse brain.
Oral glucose feeding enhances adherence of quiescent lymphocytes to fibronectin via non-canonical insulin signalling
Authors: Mallu Abhiram Charan Tej , Sivagurunathan Sivapriya , Paul Debasish , Aggarwal Hobby , Nathan Abel Arul , Ravi Mahalakshmi M. , Boppana Ramanamurthy , Jagavelu Kumaravelu , Santra Manas Kumar , Dixit Madhulika
Published: October 2021

Impaired glucose metabolism is associated with chronic inflammation, aberrant immunity and anomalous leukocyte trafficking. Conversely, infusion of functional immune cells restores glucose metabolism. Despite being exposed to periodic alterations in blood insulin levels upon fasting and feeding, studies exploring the physiological effects of these hormonal changes on quiescent circulating lymphocytes are missing. Here we find that oral glucose load in healthy men and mice enhance adherence of circulating peripheral blood mononuclear cells (PBMCs) to fibronectin. This led to increased homing of post-load PBMCs to injured blood vessels. Cell culture based experiments on Jurkat-T cells and PBMCs demonstrated that insulin elicits these adhesive effects through a non-canonical signalling involving insulin growth factor-1 receptor (IGF-1R) and phospholipase C gamma-1 (PLCγ-1) mediated activation of integrin β1. Our findings point to the relevance of post-prandial insulin spikes in regulating homing of circulating T-cells to various organs for tissue repair and immunity.

Graphical Abstract

Insulin mediates fibronectin adherence of lymphocytes through non-canonical signalling.

Insulin mediates auto-phosphorylation of IGF-1 receptor at Tyr1135leading to activation of PLC-γ1 through Tyr783 phosphorylation, which in turn leads to the activation of integrin β1 through intracellular calcium to ultimately enhance adhesion of quiescent lymphocytes to fibronectin.
Designing a comprehensive model of organizational resilience in the banking industry of Iran
Authors: Khajehpour Mahmood , Sedaghatparast Eldar , Rabieh Masood
Published: October 2021

Purpose

This research aims to design a comprehensive resilience model in the banking industry for identifying the dimensions and components that can enhance organizational resilience in the industry, which can contribute to the existing literate as a promising comprehensive model.

Design/methodology/approach

After reviewing the literature and studying the models of organizational resilience, semistructured interviews were conducted with managers and prominent experts in the banking industry. To analyze the interviews, the thematic analysis technique was used with three coding stages. After designing the research model in two main dimensions of micro and macro management in the banking industry, the relation between the main components and subcomponents was identified by using Interpretive Structural Modeling (ISM) and DEMATEL techniques.

Findings

The study findings indicating that proper observation and predicting the bank's problems and making suitable connections with the government are two major indicators of the resilience of the banking network, which can realize through influencing the components of risk management, financial resource management and system corruption. The results of this research can lead to the expansion of theoretical foundations of the past research and the concept of organizational resilience in the field of financial services and especially the banking industry.

Originality/value

This paper provides the components with a more significant impact, which bank managers should consider the relationship among them to enhance organizational resilience for more effectiveness of their decisions.
Some thoughts on establishing the theoretical system of socialist political economics with Chinese characteristics
Authors: Shen Kaiyan
Published: October 2021

Purpose

It is scholars' great mission in this era to creatively develop new implications, paradigms and discourses of China's political economy and establish a theoretical system of political economy with Chinese characteristics based on the fundamental principles of Marxist theory and the practice and historical process of Chinese economic reform, through theorizing and systemizing the practices of China's socialist market economy construction. The purpose of this paper is to give some suggestions to establish a socialist theoretical system with Chinese characteristics.

Design/methodology/approach

This paper makes a comprehensive analysis of the principles, objectives, study objects, methodologies as well as the framework of the theoretical system of the political economy with Chinese characteristics.

Findings

Additionally, starting from the unity of opposites between public ownership of resources and resource allocation in a market mechanism, which is the fundamental dialectical relation of China's socialist market economy, the authors will adopt the dual dialectical analysis approach to discover and understand the duality features of the socialist economic system with Chinese characteristics.

Originality/value

With adherence to the mission of China's socialist economic system, the goal of China's market economic reform, and the perspectives of Marxist political economy, the authors must explicitly define the so-called Chinese characteristics and then summarize the dynamics and innovations during the evolution of Chinese socialist political economy with high theory confidence and theory self-consciousness.