bluuebunny/crossref_metadata_2025_split huggingface dataset:
EvoMol: a flexible and interpretable evolutionary algorithm for unbiased de novo molecular generation
Authors: Leguy Jules , Cauchy Thomas , Glavatskikh Marta , Duval Béatrice , Da Mota Benoit 
Published: September 2020

AbstractThe objective of this work is to design a molecular generator capable of exploring known as well as unfamiliar areas of the chemical space. Our method must be flexible to adapt to very different problems. Therefore, it has to be able to work with or without the influence of prior data and knowledge. Moreover, regardless of the success, it should be as interpretable as possible to allow for diagnosis and improvement. We propose here a new open source generation method using an evolutionary algorithm to sequentially build molecular graphs. It is independent of starting data and can generate totally unseen compounds. To be able to search a large part of the chemical space, we define an original set of 7 generic mutations close to the atomic level. Our method achieves excellent performances and even records on the QED, penalised logP, SAscore, CLscore as well as the set of goal-directed functions defined in GuacaMol. To demonstrate its flexibility, we tackle a very different objective issued from the organic molecular materials domain. We show that EvoMol can generate sets of optimised molecules having high energy HOMO or low energy LUMO, starting only from methane. We can also set constraints on a synthesizability score and structural features. Finally, the interpretability of EvoMol allows for the visualisation of its exploration process as a chemically relevant tree.
Estimate of the sequenced proportion of the global prokaryotic genome
Authors: Zhang Zheng , Wang Jianing , Wang Jinlan , Wang Jingjing , Li Yuezhong 
Published: September 2020

Abstract
Background
Sequencing prokaryotic genomes has revolutionized our understanding of the many roles played by microorganisms. However, the cell and taxon proportions of genome-sequenced bacteria or archaea on earth remain unknown. This study aimed to explore this basic question using large-scale alignment between the sequences released by the Earth Microbiome Project and 155,810 prokaryotic genomes from public databases.

Results
Our results showed that the median proportions of the genome-sequenced cells and taxa (at 100% identities in the 16S-V4 region) in different biomes reached 38.1% (16.4–86.3%) and 18.8% (9.1–52.6%), respectively. The sequenced proportions of the prokaryotic genomes in biomes were significantly negatively correlated with the alpha diversity indices, and the proportions sequenced in host-associated biomes were significantly higher than those in free-living biomes. Due to a set of cosmopolitan OTUs that are found in multiple samples and preferentially sequenced, only 2.1% of the global prokaryotic taxa are represented by sequenced genomes. Most of the biomes were occupied by a few predominant taxa with a high relative abundance and much higher genome-sequenced proportions than numerous rare taxa.

Conclusions
These results reveal the current situation of prokaryotic genome sequencing for earth biomes, provide a more reasonable and efficient exploration of prokaryotic genomes, and promote our understanding of microbial ecological functions.
Reverse vaccinology assisted designing of multiepitope-based subunit vaccine against SARS-CoV-2
Authors: Tahir ul Qamar Muhammad , Shahid Farah , Aslam Sadia , Ashfaq Usman Ali , Aslam Sidra , Fatima Israr , Fareed Muhammad Mazhar , Zohaib Ali , Chen Ling-Ling 
Published: September 2020

Abstract
Background
Coronavirus disease 2019 (COVID-19) linked with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause severe illness and life-threatening pneumonia in humans. The current COVID-19 pandemic demands an effective vaccine to acquire protection against the infection. Therefore, the present study was aimed to design a multiepitope-based subunit vaccine (MESV) against COVID-19.

Methods
Structural proteins (Surface glycoprotein, Envelope protein, and Membrane glycoprotein) of SARS-CoV-2 are responsible for its prime functions. Sequences of proteins were downloaded from GenBank and several immunoinformatics coupled with computational approaches were employed to forecast B- and T- cell epitopes from the SARS-CoV-2 highly antigenic structural proteins to design an effective MESV.

Results
Predicted epitopes suggested high antigenicity, conserveness, substantial interactions with the human leukocyte antigen (HLA) binding alleles, and collective global population coverage of 88.40%. Taken together, 276 amino acids long MESV was designed by connecting 3 cytotoxic T lymphocytes (CTL), 6 helper T lymphocyte (HTL) and 4 B-cell epitopes with suitable adjuvant and linkers. The MESV construct was non-allergenic, stable, and highly antigenic. Molecular docking showed a stable and high binding affinity of MESV with human pathogenic toll-like receptors-3 (TLR3). Furthermore, in silico immune simulation revealed significant immunogenic response of MESV. Finally, MEV codons were optimized for its in silico cloning into the Escherichia coli K-12 system, to ensure its increased expression.

Conclusion
The MESV developed in this study is capable of generating immune response against COVID-19. Therefore, if designed MESV further investigated experimentally, it would be an effective vaccine candidate against SARS-CoV-2 to control and prevent COVID-19.
Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system
Authors: Huang Jing , Jia Yuntao , Sun Shusen , Meng Long 
Published: September 2020

Abstract
Background
To describe and analyze the patterns of adverse events associated with dipeptidyl peptidase-4 inhibitors (DPP-4is) (sitagliptin, saxagliptin, linagliptin, vildagliptin, and alogliptin) from the FDA Adverse Event Reporting System (FAERS) and to highlight areas of safety concerns.

Methods
Adverse events spontaneously submitted to the FAERS between 2004 Q1 to 2019 Q2 were included. The online tool OpenVigil 2.1 was used to query the database. The research relied on definitions of preferred terms (PTs) specified by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ). The reporting odds ratio (ROR), with 95% confidence intervals (CIs) was calculated for disproportionality analysis.

Results
Over 16 years, a total of 9706 adverse event reports were identified. Alogliptin was excluded from further analysis due to insufficient sample size. Compared with the non-insulin antidiabetic drugs, the four DPP-4is were all disproportionately associated with four SMQs: “gastrointestinal nonspecific inflammation and dysfunctional conditions,” “hypersensitivity,” “severe cutaneous adverse reactions,” and “noninfectious diarrhoea”. As for PT level analyses, DPP-4is are associated with higher reporting of the gastrointestinal tract, pancreas, malignancies, infection, musculoskeletal disorders, general disorders, hypersensitivity, and skin AEs.

Conclusions
Data mining of the FAERS is useful for examining DPP-4 inhibitors-associated adverse events. The findings of the present study are compatible with clinical experience, and it provides valuable information to decision-makers and healthcare providers in clinical practice.
Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL
Authors: Liu Wen-Hsin , Mrozek-Gorska Paulina , Wirth Anna-Katharina , Herold Tobias , Schwarzkopf Larissa , Pich Dagmar , Völse Kerstin , Melo-Narváez M. Camila , Carlet Michela , Hammerschmidt Wolfgang , Jeremias Irmela 
Published: September 2020

Abstract
Background
Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors, from the vast amount of tumor descriptive expression data.

Methods
We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap.

Results
With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4.

Conclusion
Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
Biocontrol potential of Streptomyces sp. CACIS-1.5CA against phytopathogenic fungi causing postharvest fruit diseases
Authors: Evangelista-Martínez Zahaed , Contreras-Leal Erika Anahí , Corona-Pedraza Luis Fernando , Gastélum-Martínez Élida 
Published: September 2020

Abstract
Background
Fungi are one of the microorganisms that cause most damage to fruits worldwide, affecting their quality and consumption. Chemical controls with pesticides are used to diminish postharvest losses of fruits. However, biological control with microorganisms or natural compounds is an increasing alternative to protect fruits and vegetables. In this study, the antifungal effect of Streptomyces sp. CACIS-1.5CA on phytopathogenic fungi that cause postharvest tropical fruit rot was investigated.

Main body
Antagonistic activity was evaluated in vitro by the dual confrontation over fungal isolates obtained from grape, mango, tomato, habanero pepper, papaya, sweet orange, and banana. The results showed that antagonistic activity of the isolate CACIS-1.5CA was similar to the commercial strain Streptomyces lydicus WYEC 108 against the pathogenic fungi Colletotrichum sp., Alternaria sp., Aspergillus sp., Botrytis sp., Rhizoctonia sp., and Rhizopus sp. with percentages ranging from 30 to 63%. The bioactive extract obtained from CACIS-1.5 showed a strong inhibition of fungal spore germination, with percentages ranging from 92 to 100%. Morphological effects as irregular membrane border, deformation, shrinkage, and collapsed conidia were observed on the conidia. Molecularly, the biosynthetic clusters of genes for the polyketide synthase (PKS) type I, PKS type II, and NRPS were detected in the genome of Streptomyces sp. CACIS-1.5CA.

Conclusions
This study presented a novel Streptomyces strain as a natural alternative to the use of synthetic fungicides or other commercial products having antagonistic microorganisms that were used in the postharvest control of phytopathogenic fungi affecting fruits.
UndetectableRAS-Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients WithRAS-Mutant Metastatic Colorectal Cancer
Authors: Bouchahda Mohamed , Saffroy Raphael , Karaboué Abdoulaye , Hamelin Jocelyne , Innominato Pasquale , Saliba Faouzi , Lévi Francis , Bosselut Nelly , Lemoine Antoinette 
Published: September 2020

PURPOSECombining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with RAS wild-type ( RAS-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with RAS mutation ( RAS-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was RAS-wt.MATERIALS AND METHODSThe occurrence of Kirsten rat sarcoma viral oncogene homolog ( KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 ( BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti–epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-mt ctDNA were treated with the oncologist’s choice of therapy.RESULTSOf 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified RAS-mt in seven patients (44%) and RAS-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.CONCLUSIONPatients with RAS-mt mCRC whose plasma biopsies contained RAS-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
Inhibition of BRAF Sensitizes Thyroid Carcinoma to Immunotherapy by Enhancing tsMHCII-mediated Immune Recognition
Authors: Zhi Jingtai , Zhang Peitao , Zhang Wei , Ruan Xianhui , Tian Mengran , Guo Shicheng , Zhang Weiyu , Zheng Xiangqian , Zhao Li , Gao Ming 
Published: September 2020

AbstractContextMultiple mechanisms play roles in restricting the ability of T-cells to recognize and eliminate tumor cells.ObjectiveTo identify immune escape mechanisms involved in papillary thyroid carcinoma (PTC) to optimize immunotherapy.Setting and DesigniTRAQ analysis was conducted to identify proteins differentially expressed in PTC samples with or without BRAFV600E mutation. Molecular mechanisms regulating tumor cell evasion were investigated by in vitro modulations of BRAF/MAPK and related pathways. The pathological significance of identified tumor-specific major histocompatibility complex class II (tsMHCII) molecules in mediating tumor cell immune escape and targeted immune therapy was further evaluated in a transgenic mouse model of spontaneous thyroid cancer.ResultsProteomic analysis showed that tsMHCII level was significantly lower in BRAFV600E-associated PTCs and negatively correlated with BRAF mutation status. Constitutive activation of BRAF decreased tsMHCII surface expression on tumor cells, which inhibited activation of CD4+ T-cells and led to immune escape. Pathway analysis indicated that the transforming growth factor (TGF)-β1/SMAD3-mediated repression of tsMHCII, which could be reversed by BRAF inhibition (BRAFi). Targeting this pathway with a combined therapy of BRAF inhibitor PLX4032 and anti-PD-1 antibody efficiently blocked tumor growth by increasing CD4+ T-cell infiltration in a transgenic PTC mouse model.ConclusionsOur results suggest that BRAFV600E mutation in PTC impairs the expression of tsMHCII through the TGF-β1/SMAD3 pathway to enhance immune escape. Combined treatment with PLX4032 and anti-PD-1 antibody promotes recognition and elimination of PTC by the immune system in a pre-clinical mouse model, and therefore offers an effective therapeutic strategy for patients with advanced PTC.
Prenatal Androgenization Alters the Development of GnRH Neuron and Preoptic Area RNA Transcripts in Female Mice
Authors: Burger Laura L , Wagenmaker Elizabeth R , Phumsatitpong Chayarndorn , Olson David P , Moenter Suzanne M 
Published: September 2020

Abstract
Polycystic ovary syndrome (PCOS) is the most common form of infertility in women. The causes of PCOS are not yet understood and both genetics and early-life exposure have been considered as candidates. With regard to the latter, circulating androgens are elevated in mid–late gestation in women with PCOS, potentially exposing offspring to elevated androgens in utero; daughters of women with PCOS are at increased risk for developing this disorder. Consistent with these clinical observations, prenatal androgenization (PNA) of several species recapitulates many phenotypes observed in PCOS. There is increasing evidence that symptoms associated with PCOS, including elevated luteinizing hormone (LH) (and presumably gonadotropin-releasing hormone [GnRH]) pulse frequency emerge during the pubertal transition. We utilized translating ribosome affinity purification coupled with ribonucleic acid (RNA) sequencing to examine GnRH neuron messenger RNAs from prepubertal (3 weeks) and adult female control and PNA mice. Prominent in GnRH neurons were transcripts associated with protein synthesis and cellular energetics, in particular oxidative phosphorylation. The GnRH neuron transcript profile was affected more by the transition from prepuberty to adulthood than by PNA treatment; however, PNA did change the developmental trajectory of GnRH neurons. This included families of transcripts related to both protein synthesis and oxidative phosphorylation, which were more prevalent in adults than in prepubertal mice but were blunted in PNA adults. These findings suggest that prenatal androgen exposure can program alterations in the translatome of GnRH neurons, providing a mechanism independent of changes in the genetic code for altered expression.
Sleep-length differences are associated with altered longevity in the fruit fly Drosophila melanogaster
Authors: Thompson Jacqueline B. , Su Oanh Oanh , Yang Nou , Bauer Johannes H. 
Published: September 2020

ABSTRACT
Sleep deprivation has been shown to negatively impact health outcomes, leading to decreased immune responses, memory loss, increased activity of stress and inflammatory pathways, weight gain, and even behavioral changes. These observations suggest that sleep deprivation substantially interferes with important physiological functions, including metabolic pathways of energy utilization. Many of those phenotypes are correlated with age, suggesting that disrupted sleep may interfere with the aging process. However, little is known about how sleep disruption affects aging and longevity. Here, we investigate this relationship using eight representative fruit fly lines from the Sleep Inbred Panel (SIP). The SIP consists of 39 inbred lines that display extreme short- and long-sleep patterns, and constitutes a crucial Drosophila community resource for investigating the mechanisms of sleep regulation. Our data show that flies with short-sleep periods have ∼16% longer life span, as well as reduced aging rate, compared to flies with long-sleep. In contrast, disrupting normal circadian rhythm reduces fly longevity. Short-sleep SIP flies moreover show slight metabolic differences to long-sleep lines, and to flies with disrupted circadian rhythm. These data suggest that the inbred SIP lines engage sleep mechanisms that are distinct from the circadian clock system.
The ESCRTs – converging on mechanism
Authors: Remec Pavlin Mark , Hurley James H. 
Published: September 2020

ABSTRACT
The endosomal sorting complexes required for transport (ESCRTs) I, -II and –III, and their associated factors are a collection of ∼20 proteins in yeast and ∼30 in mammals, responsible for severing membrane necks in processes that range from multivesicular body formation, HIV release and cytokinesis, to plasma and lysosomal membrane repair. ESCRTs are best known for ‘reverse-topology’ membrane scission, where they act on the inner surface of membrane necks, often when membranes are budded away from the cytosol. These events are driven by membrane-associated assemblies of dozens to hundreds of ESCRT molecules. ESCRT-III proteins form filaments with a variety of geometries and ESCRT-I has now been shown to also form helical structures. The complex nature of the system and the unusual topology of its action has made progress challenging, and led to controversies with regard to its underlying mechanism. This Review will focus on recent advances obtained by structural in vitro reconstitution and in silico mechanistic studies, and places them in their biological context. The field is converging towards a consensus on the broad outlines of a mechanism that is driven by a progressive ATP-dependent treadmilling exchange of ESCRT subunits, as well as compositional change and geometric transitions in ESCRT filaments.
Overexpression of Mdm36 reveals Num1 foci that mediate dynein-dependent microtubule sliding in budding yeast
Authors: Omer Safia , Brock Katia , Beckford John , Lee Wei-Lih 
Published: September 2020

ABSTRACT
The current model for spindle positioning requires attachment of the microtubule (MT) motor cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect spindle displacement. How dynein is anchored by cortical attachment machinery to generate large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the yeast dynein attachment molecule, is limited by its assembly factor Mdm36. Overexpression of Mdm36 results in an overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that mediate dynein anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 clusters containing around only six Num1 molecules mediate dynein-dependent spindle pulling via a lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with mitochondrial tethering but do not interfere with the dynein-based spindle-pulling function of Num1. We propose that formation of small ensembles of attachment molecules is sufficient for dynein anchorage and cortical generation of large spindle-pulling forces.
This article has an associated First Person interview with the first author of the paper.
Assessment of the Personnel Potential of Production Masters Using the Method of Identifying Qualification Deficiencies (on the Example of a Study Conducted in JSC «Kuznetsov»)
Authors: Komarov V. , Fedorchenko G. 
Published: September 2020

The article describes the study of the personnel potential of the production masters of a large industrial enterprise. Such studies are of great practical importance, because they reveal hidden reserves associated with insufficient use of human resources, and therefore allow you to find additional ways to improve the efficiency of the organization, increase productivity. The main method of assessing the human resources potential in the article is the method of identifying qualification deficits-indicators that reflect not achieving the required level for a specific competence, lack of specific knowledge or skills, a certain skill in the work of certain employees.
In conditions of increasing changes in all spheres of human life, increasing competition of technologies, services, and goods, the ability of an organization to respond quickly to these changes, correctly assess the skill level of its employees, understand what skill deficits are occurring, and take timely measures to eliminate them is of great importance.
Assess workforce capacity and identify the skill deficits is to obtain reliable and objective data reflecting the quality of human resources of the organization, on which to build effective program of individual and group staff development, which in turn will improve the overall efficiency of the organization.
The article describes the research process itself, its stages and their features, and the main results. The novelty of the study is that a new approach is applied to the formation of indicators for assessing human resources potential, which is demonstrated by a specific example.