bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiological profile and clinical conditions of women with or without precursorlesion for cervical cancer
Authors: de França Lyvia Mirelle Carneiro , Galvão Caroline Ramalho , Galvão Lorena Ramalho , Cirqueira Silva Maria Emília , Silva Dantas Bruna Matos , de Assis Sampaio Lorena Moura , das Mercês Magno Conceição , Conceição Sarah dos Santos , Silva Roberta Borges , Freitas Coelho Julita Maria
Published: June 2021

Introduction

Cervical Cancer (CC) in Brazil is the fourth cause of death for malignant neoplasms in female population, being expected to 16,370 new cases for the biennium 2018-2019.

Objective

To identify factors associated with the presence of cytopathological changes of the cervix, HIV and/or syphilis in women who performed the Pap Smear (PS) at Family Health Unit (FHU) San Martin, in Salvador-BA, 09 March 2015 to 2018.

Materials and methods

This cross-sectional study consisted of 150 participants. After application of a questionnaire, there was conducted clinical examination of the breast and gynecological and rapid tests for diagnosis of syphilis and HIV types 1 and 2. The bivariate analysis was made by associating each one of the independent variables with the outcome, through contingency tables (Chi-square test and when necessary, the Fisher’s exact test). The estimates were obtained with Prevalence Ratio (PR) with their 95% confidence intervals (CI 95%) and p values. Mean differences were estimated through Student’s t-test. The goodness of the test was estimated by ratio of maximum likelihood (p ≤ 0.05).

Results

There were 11.33% of women with injury and 88.67% without injury. The group with injury (n = 17) presented the worst values in relation to the use of the cigarette (17.65% vs 3.76%) and clinical examination in breast change issues (17.65% vs 4.51%) and unloading (11.76% vs papillary 1.50%), in comparison to the group without precursor lesion pro CC, statistically significant (p ≤ 0.05). 5 cases were positive for syphilis (3.33%), and no case of HIV types 1 and 2.

Discussion

The study confirmed risk factors for injury precursors of CC, such as smoking and mammary changes, as well as how much research related to diverged condom use and reducing the risk of injury and the likely Association with Sexually Transmitted Infections (STI).

Conclusion

There was detected a low percentage of women with precursor lesions for the CC (11.33%), that were not associated with syphilis and HIV types 1 and 2, but were correlated the expected factors like mammary changes and smoking. The reorganization of actions of active search of women with risk factors for CC for the EP can culminate in the reduction of this cancer.

Descriptors

Pap Smear; Precursor Lesion; Cervical Cancer.
Secondary metabolism drives ecological breadth in the Xylariaceae
Authors: Franco Mario E.E. , Wisecaver Jennifer H. , Arnold A. Elizabeth , Ju Yu-Ming , Slot Jason C. , Ahrendt Steven , Moore Lillian P. , Eastman Katharine E. , Scott Kelsey , Konkel Zachary , Mondo Stephen J. , Kuo Alan , Hayes Richard , Haridas Sajeet , Andreopoulos Bill , Riley Robert , LaButti Kurt , Pangilinan Jasmyn , Lipzen Anna , Amirebrahimi Mojgan , Yan Juying , Adam Catherine , Keymanesh Keykhosrow , Ng Vivian , Louie Katherine , Northen Trent , Drula Elodie , Henrissat Bernard , Hsieh Huei-Mei , Youens-Clark Ken , Lutzoni François , Miadlikowska Jolanta , Eastwood Daniel C. , Hamelin Richard C. , Grigoriev Igor V. , U’Ren Jana M.
Published: June 2021

Global, large-scale surveys of phylogenetically diverse plant and lichen hosts have revealed an extremely high richness of endophytes in the Xylariales, one of the largest clades of filamentous fungi and a significant source of novel secondary metabolites (SMs). Endophytes may produce host protective antimicrobial or insecticidal SMs, as well as compounds that facilitate symbiotic establishment through suppression or degradation of host immune response, but the ecological roles of most SMs are unknown. Here we characterized metabolic gene clusters in 96 genomes of endophytes and closely related saprotrophs and pathogens in two clades of Xylariales (Xylariaceae s.l. and Hypoxylaceae). Hundreds of genes appear horizontally transferred to xylarialean fungi from distantly related fungi and bacteria, including numerous genes in secondary metabolite gene clusters (SMGCs). Although all xylarialean genomes contain hyperabundant SMGCs, we show that increased gene duplications, horizontal gene transfers (HGTs), and SMGC content in Xylariaceae s.l. taxa are linked to greater phylogenetic host breadth, larger biogeographic distributions, and increased capacity for lignocellulose decomposition compared to Hypoxylaceae taxa. Overall, our results suggest that xylarialean endophytes capable of dual ecological modes (symbiotic and saprotrophic) experience greater selection to diversify SMGCs to both increase competitiveness within microbial communities and facilitate diverse symbiotic interactions.
Species-specific effects of cation channel TRPM4 small-molecule inhibitors
Authors: Arullampalam Prakash , Preti Barbara , Ross-Kaschitza Daniela , Lochner Martin , Rougier Jean-Sébastien , Abriel Hugues
Published: June 2021

Background

The Transient Receptor Potential Melastatin member 4 (TRPM4) gene encodes a calcium-activated non-selective cation channel expressed in several tissues. Mutations in TRPM4 have been reported in patients with different types of cardiac conduction defects. It is also linked to immune response and cancers, but the associated molecular mechanisms are still unclear. Thus far, 9-phenanthrol is the most common pharmacological compound used to investigate TRPM4 function. We recently identified two promising aryloxyacyl-anthranilic acid compounds (abbreviated CBA and NBA) inhibiting TRPM4. However, all afore-mentioned compounds were screened using assays expressing human TRPM4, whereas the efficacy on mouse TRPM4 has not been assessed. Mouse models are essential to investigate ion channel physiology and chemical compound efficacy.

Aim

In this study, we performed comparative electro-physiology experiments to assess the effect of these TRPM4 inhibitors on human and mouse TRPM4 channels heterologously expressed in TsA-201 cells.

Methods and Results

We identified striking species-dependent differences in TRPM4 responses. NBA inhibited both human and mouse TRPM4 currents when applied intracellularly and extracellularly using excised membrane patches. CBA inhibited human TRPM4, both intracellularly and extracellularly. Unexpectedly, the application of CBA had no inhibiting effect on mouse TRPM4 current when perfused on the extracellular side. Instead, it increased mouse TRPM4 current at negative holding potentials. In addition, CBA on the intracellular side altered the outward rectification component of the mouse TRPM4 current. Application of 9-phenanthrol, both intracellularly and extracellularly, inhibited human TRPM4. For mouse TRPM4, 9-phenanthrol perfusion led to opposite effects depending on the site of application. With intracellular 9-phenanthrol, we observed a tendency towards potentiation of mouse TRPM4 outward current at positive holding potentials.

Conclusion

Altogether, these results suggest that pharmacological compounds screened using “humanised assays” should be extensively characterised before application in in vivo mouse models.
Birth Order Differences in Education Originate in Post-Natal Environments
Authors: Isungset Martin Arstad , Freese Jeremy , Andreassen Ole A. , Lyngstad Torkild Hovde
Published: June 2021

Siblings share many environments and much of their genetics. Yet, siblings turn out different. Intelligence and education are influenced by birth order, with earlier-born siblings outperforming later-borns. We investigate whether birth order differences in education are caused by biological differences present at birth, that is, genetic differences or in-utero differences. Using family data that spans two generations, combining registry, survey, and genotype information, this study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). We show that there are no genetic differences by birth order as captured by polygenic scores (PGSs) for educational attainment. Furthermore, we show that earlier-born have lower birth weight than later-born, indicating worse uterine environments. Educational outcomes are still higher for earlier-born children when we adjust for PGSs and in utero variables, indicating that birth order differences arise post-natally. Finally, we consider potential environmental influences, such as differences according to maternal age, parental educational attainment, and sibling genetic nurture. We show that birth order differences are not biological in origin, but pinning down their specific causes remains elusive.
A functionally divergent intrinsically disordered region underlying the conservation of stochastic signaling
Authors: Hsu Ian S , Strome Bob , Lash Emma , Robbins Nicole , Cowen Leah E , Moses Alan M
Published: June 2021

Stochastic signaling dynamics expand living cells’ information processing capabilities. An increasing number of studies report that regulators encode information in their pulsatile dynamics. The evolutionary mechanisms that lead to complex signaling dynamics remain uncharacterized, perhaps because key interactions of signaling proteins are encoded in intrinsically disordered regions (IDRs), whose evolution is difficult to analyze. Here we focused on the stochastic pulsing dynamics of Crz1, a transcription factor in fungi downstream of the widely conserved calcium signaling pathway. We find that Crz1 IDRs from anciently diverged fungi can all respond transiently to calcium stress; however, only Crz1 IDRs from the Saccharomyces clade support pulsatility, encode extra information, and rescue fitness, while the Crz1 IDRs from distantly related fungi do none of the three. On the other hand, we find that Crz1 pulsing is conserved in the distantly related fungi, consistent with the evolutionary model of stabilizing selection. Further, we show that a calcineurin docking site in a specific part of the IDRs appears to be sufficient for pulsing and show evidence for a beneficial increase in the relative calcineurin affinity of this docking site. We propose that evolutionary flexibility of functionally divergent IDRs underlies the conservation of stochastic signaling by stabilizing selection.
Interference at Influenza Hemagglutinin Antigenic-Sites Determines Antibody Levels and Specificities after Repeat Vaccination
Authors: Anderson Christopher S. , Topham David J.
Published: June 2021

Background

It is recommended that children receive a dose of the influenza vaccine at 6 months of age and a second dose the following season. In some years, the second dose will be the same vaccine formulation, in others years it with be re-formulated to include HA proteins derived from antigenically drifted or shifted circulating influenza strains. In addition, natural exposure to influenza can create permanent changes to the memory B cell repertoire and specificities. The effect that the specificity of pre-existing humoral immunity has on antibody levels and specificity after repeat vaccination is an ongoing research area.

Methods

We used a computational framework (ssMod.v1) to simulate scenarios that occurred during the 2009 influenza pandemic: children receiving a second dose who have previously exposed to the 2009 influenza HA antigen, children previously exposed to an HA antigen antigenically similar to the 2009 influenza HA antigen, and children previously exposed to an antigenically dissimilar strain. To assess the contribution of pre-existing immunity, two experimental permutations in the sMod.v1 were made: elimination of antibody-mediated antibody clearance of vaccine (HA) antigen by pre-existing antibodies and elimination of the ability of memory B cells to form germinal centers. In the simulation, 30 days after repeat vaccination antibody specificities were examined against 12 antigenically historical vaccine/HA variant influenza strains for each of the five canonical antigenic-sites and the subdominant, conserved, stalk antigenic-site.

Results

We found that elimination of antibody-mediated antigen clearance significantly increased antibody levels while elimination of the ability of memory B cells to form germinal center reactions significantly decreased the total antibody levels, but this was dependent on the antigenic relationship between the original vaccine and repeat vaccine and the particular antigenic-site. Moreover, highly-cross-reactive antibody was highest when the antigenic distance between original vaccine HA antigen and repeat vaccine HA antigen was larger and antibody-mediated antigen clearance was eliminated.
SARS-CoV-2 Spreads through Cell-to-Cell Transmission
Authors: Zeng Cong , Evans John P. , King Tiffany , Zheng Yi-Min , Oltz Eugene M. , Whelan Sean P. J. , Saif Linda , Peeples Mark E. , Liu Shan-Lu
Published: June 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While ACE2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the variants of concern (VOC) B.1.1.7 and B.1.351 have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccine sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.
Mitochondrial Contact Site and Cristae Organizing System (MICOS) Machinery Supports Heme Biosynthesis by Enabling Optimal Performance of Ferrochelatase
Authors: Dietz Jonathan V. , Willoughby Mathilda M. , Piel Robert B. , Ross Teresa A. , Bohovych Iryna , Addis Hannah G. , Fox Jennifer L. , Lanzilotta William N. , Dailey Harry A. , Wohlschlegel James A. , Reddi Amit R. , Medlock Amy E. , Khalimonchuk Oleh
Published: June 2021

Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied, and all the biosynthetic enzymes have been structurally characterized to varying extents. Nevertheless, our understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Herein we investigate the molecular organization as well as the catalytic and structural features of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae. Biochemical and genetic analyses reveal dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity and results in accumulation of highly reactive and potentially toxic tetrapyrrole precursors that may result in oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. Our data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.
Intracerebral mechanisms explaining the impact of incidental feedback on mood state and risky choice
Authors: Cecchi Romane , Vinckier Fabien , Hammer Jiri , Marusic Petr , Nica Anca , Rheims Sylvain , Trebuchon Agnès , Barbeau Emmanuel , Denuelle Marie , Maillard Louis , Minotti Lorella , Kahane Philippe , Pessiglione Mathias , Bastin Julien
Published: June 2021

Identifying factors whose fluctuations are associated with choice inconsistency is a major issue for rational decision theory. Here, we investigated the neuro-computational mechanisms through which mood fluctuations may bias human choice behavior. Intracerebral EEG data were collected in a large group of participants (n = 30), while they were performing interleaved quiz and choice tasks. Neural baseline activity preceding choice onset was confronted first to mood level, estimated by a computational model integrating the feedbacks received in the quiz task, and then to the weighting of option attributes, in a computational model predicting risk attitude in the choice task. Results showed that 1) elevated broadband gamma activity (BGA) in the ventromedial prefrontal cortex (vmPFC) and dorsal anterior insula (daIns) was respectively signaling periods of high and low mood, 2) increased vmPFC and daIns BGA respectively promoted and tempered risk taking by overweighting gain versus loss prospects. Thus, incidental feedbacks induce brain states that correspond to different moods and bias the comparison of safe and risky options. More generally, these findings might explain why people experiencing positive (or negative) outcome in some part of their life tend to expect success (or failure) in any other.
Simulating brain signals with predefined mutual correlations – a technical note
Authors: Moiseev Alexander
Published: June 2021

Objective

When modeling task-related human brain activity it is often necessary to simulate brain signals with specific mutual correlations between them. The signals should resemble those observed in practice, and consist of an “evoked” (“phase-locked”) component and a random oscillatory part. To be neurophysiologically plausible their waveforms must be shaped in a certain way or exhibit specific global features; in technical terms - they should be modulated by a certain envelope function. The goal of this technical note is to describe a simple way of how such signal sets can be obtained.

Methods

We derive a procedure which allows generating multi-epoch signals with the above properties. This is done by mixing a “seed” set of waveforms typically reflecting particular qualities of the target brain activity. As an example, the seed set can consist of realizations of colored noise with desired power spectrum, or can be obtained from real brain measurements.

Results

The algorithm yields a set of n multi-epoch signals with specified mutual correlations. Evoked parts, oscillatory parts and global envelopes of the signals can be controlled independently in order to obtain desired properties of the generated time courses.

Conclusion

The procedure provides versatile sets of mutually correlated signals suitable for modeling task-related brain activity.

Significance

In contrast to other methods often relying on complicated computations, the suggested approach is straightforward and easy to apply in everyday practical work, yet yielding realistic “functionally connected” simulated brain signals.
Molecular characterization of inversion breakpoints in theDrosophila nasutaspecies group
Authors: Mai Dat , Bachtrog Doris
Published: June 2021

Chromosomal inversions are fundamental drivers of genome evolution. In theDrosophilagenus, inversions have been widely characterized cytologically, and play an important role in local adaptation. Here, we characterize chromosomal inversions in theDrosophila nasutaspecies group using chromosome-level, reference-quality assemblies of seven species and subspecies in this clade. Reconstruction of ancestral karyotypes allowed us to infer the order in which the 22 identified inversions occurred along the phylogeny. We found a higher rate of inversions on the X chromosome, and heterogeneity in the rate of accumulation across the phylogeny. We molecularly characterize the breakpoints of six autosomal inversions, and found that repeated sequences are associated with inversion breakpoints in four of these inversions, suggesting that ectopic recombination is an important mechanism in generating inversion. Characterization of inversions in this species group provides a foundation for future population genetic and functional studies in this recently diverged species group.
The Rab11-Family Interacting Proteins reveal selective interaction of mammalian recycling endosomes with the Toxoplasma parasitophorous vacuole in a Rab11- and Arf6-dependent manner
Authors: Hartman Eric J. , Romano Julia D. , Coppens Isabelle
Published: June 2021

After invasion of mammalian cells, the parasite Toxoplasma gondii multiplies in a self-made membrane-bound compartment, the parasitophorous vacuole (PV). We previously showed that intravacuolar Toxoplasma interacts with many host cell organelles, especially recycling endosomes, and further manipulates the host endocytic recycling through the sequestration of Rab11 vesicles into the PV. Mammalian Rab-PV interactions are likely mediated by Toxoplasma and host proteins that remain to be identified. In this context, we have examined the specificity of host Rab vesicle interaction with the PV by monitoring the recruitment of subtypes of Rab11 vesicles differing in their composition in Rab11-Family Interacting Proteins (FIPs). We found that vesicles with FIPs from Class I (FIP1C, FIP2, FIP5) or Class II (FIP3, FIP4) are distributed at the PV and detected to varying degrees inside the PV. The PV delivery of vesicles with FIPs from Class I, but not Class II, is Rab11-dependent. In addition to Rab11, FIP3 binds to Arf6, and vesicles associated with FIP3-Arf6 complexes are observed within the PV. Binding of FIP3 to either Rab11 or Arf6 significantly increases the internalization of vesicles into the PV. These data point to a selective process of host recycling endosome recognition and scavenging mediated by Toxoplasma.
Structural Dynamics and Catalytic Mechanism of ATP13A2 (PARK9) from Simulations
Authors: Mateeva Teodora , Klähn Marco , Rosta Edina
Published: June 2021

ATP13A2 is a gene encoding a protein of the P5B subfamily of ATPases and is a PARK gene. Molecular defects of the gene are mainly associated with variations of Parkinson’s Disease (PD). Despite the established importance of the protein in regulating neuronal integrity, the three-dimensional structure of the protein currently remains unresolved crystallographically. We have modelled the structure and reactivity of the full-length protein in its E1-ATP state. Using Molecular Dynamics (MD), Quantum cluster and Quantum Mechanical/Molecular mechanical (QM/MM) methods, we aimed at describing the main catalytic reaction, leading to the phosphorylation of Asp513. Our MD simulations suggest that two positively charged Mg2+ cations are present at the active site during the catalytic reaction, stabilizing a specific triphosphate binding mode. Using QM/MM calculations, we subsequently calculated the reaction profiles for the phosphoryl transfer step in the presence of one and two Mg2+ cations. The calculated barrier heights in both cases are found to be ∼12.5 and 7.0 kcal mol-1, respectively. We elucidated details of the catalytically competent ATP conformation and the binding mode of the second Mg2+ cofactor. We also examined the role of the conserved Arg686 and Lys859 catalytic residues. We observed that by lowering significantly the barrier height of the ATP cleavage reaction, Arg686 had significant effect on the reaction. The removal of Arg686 increased the barrier height for the ATP cleavage by more than 5.0 kcal mol-1 while the removal of key electrostatic interactions created by Lys859 to the γ-phosphate and Asp513 destabilizes the reactant state. When missense mutations occur in close proximity to an active site residue, they can interfere with the barrier height of the reaction, which can halt the normal enzymatic rate of the protein. We also found large binding pockets in the full-length structure, including a transmembrane domain pocket, which is likely where ATP13A2 cargo binds.
PLK1 inhibition selectively kills ARID1A deficient cells through uncoupling of oxygen consumption from ATP production
Authors: Srinivas Upadhyayula S. , Ramachandran Gokula K. , Wardyn Joanna D. , Hoppe Michal M. , Peng Yanfen , Lim Sherlly , Lee May Yin , Peethala Praveen C. , An Omer , Shendre Akshay , Tan Bryce W.Q. , Norbert Tay S.C. , Jaynes Patrick , Hu Longyu , Jakhar Rekha , Sachaphibulkij Karishma , Lim Lina H.K. , Crasta Karen , Yang Henry , Tan Patrick , Kappei Dennis , Peng Yong Wei , Tan David S.P. , Pervaiz Shazib , Bordi Matteo , Campello Silvia , Tam Wai Leong , Frezza Christian , Jeyasekharan Anand D.
Published: June 2021

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2-M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knocked-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/ expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of a key subunit of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.

Statement of significance

Currently, no predictive biomarkers have been identified for PLK1 inhibitors in cancer treatment. We show that ARID1A loss sensitizes cells to PLK1 inhibitors through a previously unrecognized vulnerability in mitochondrial oxygen metabolism.
scRegulocity: Detection of local RNA velocity patterns in embeddings of single cell RNA-Seq data
Authors: Harmanci Akdes Serin , Harmanci Arif O , Zhou Xiaobo , Deneen Benjamin , Rao Ganesh , Klisch Tiemo , Patel Akash
Published: June 2021

Single cell RNA-sequencing has revolutionized transcriptome analysis. ScRNA-seq provides a massive resource for studying biological phenomena at single cell level. One of the most important applications of scRNA-seq is the inference of dynamic cell states through modeling of transcriptional dynamics. Understanding the full transcriptional dynamics using the concept named RNA Velocity enables us to identify cell states, regimes of regulatory changes in cell states, and putative drivers within these states. We present scRegulocity that integrates RNA-velocity estimates with locality information from cell embedding coordinates. scRegulocity focuses on velocity switching patterns, local patterns where velocity of nearby cells change abruptly. These different transcriptional dynamics patterns can be indicative of transitioning cell states. scRegulocity annotates these patterns with genes and enriched pathways and also analyzes and visualizes the velocity switching patterns at the regulatory network level. scRegulocity also combines velocity estimation, pattern detection and visualization steps.
Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging
Authors: Andrianov Grigorii V. , Ong Wern Juin Gabriel , Serebriiskii Ilya , Karanicolas John
Published: June 2021

In early stage drug discovery, the hit-to-lead optimization (or “hit expansion”) stage entails starting from a newly-identified active compound, and improving its potency or other properties. Traditionally this process relies on synthesizing and evaluating a series of analogs to build up structure-activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogs with improved potency. Our protocol begins from an inhibitor of the target kinase, and generalizes the synthetic route used to access it. By searching for commercially-available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions – or billions – of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well-described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into a single new compounds, and which are not. Further, the use of the pairwise approximation allows interaction energies to be assigned to each compound in the library, without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments, and the reduced computational requirements allow for flexible energy minimizations that allow the kinase to respond to each substitution. We demonstrate this protocol using libraries built from six representative kinase inhibitors drawn from the literature, which target five different kinases: CDK9, CHK1, CDK2, EGFRT790M, and ACK1. In each example, the enumerated library includes additional analogs reported by the original study to have activity, and these analogs are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

Graphical Abstract
A subset of CB002 xanthine analogues bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53
Authors: Hernández Borrero Liz J. , Dicker David T. , Santiago John , Sanders Jennifer , Tian Xiaobing , Ahsan Nagib , Lev Avital , Zhou Lanlan , El-Deiry Wafik S.
Published: June 2021

Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes including metastasis and therapy resistance. CB002 and structural-analogues restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2-checkpoint. Novel CB002-analogues induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogues target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression and downregulation of essential proteins in DNA-synthesis and -repair. CB002-analogue #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminaryin vivostudies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs show activation of p53 pathway signaling in tumors with mutated p53, and target an S-phase checkpoint.
Evaluating sources of technical variability in the mechano-node-pore sensing pipeline and their effect on the reproducibility of single-cell mechanical phenotyping
Authors: Li Brian , Cotner Kristen L. , Liu Nathaniel K. , Hinz Stefan , LaBarge Mark A. , Sohn Lydia L.
Published: June 2021

Cellular mechanical properties can reveal physiologically relevant characteristics in many cell types, and several groups have developed microfluidics-based platforms to perform single-cell mechanical testing with high throughput. However, prior work has performed only limited characterization of these platforms’ technical variability and reproducibility. Here, we evaluate the repeatability performance of mechano-node-pore sensing, which is a single-cell mechanical phenotyping platform developed by our research group. We measured the degree to which device-to-device variability and semi-manual data processing affected this platform’s measurements of single-cell mechanical properties, and we demonstrated high repeatability across the entire technology pipeline even for novice users. We then compared results from identical mechano-node-pore sensing experiments performed by researchers in two different labs with different analytical instruments, demonstrating that the mechanical testing results from these two locations are in agreement. Our findings quantify the expectation of technical variability in mechano-node-pore sensing even in minimally experienced hands. Most importantly, we find that the repeatability performance we measured is fully sufficient for interpreting biologically relevant single-cell mechanical measurements with high confidence.
Significant (Z|−4|) admixture signal with a source from ancient Wusun observed in contemporary Bulgarians
Authors: Stamov Svetoslav
Published: June 2021

We report the presence of significant Central Asian ancestry in both contemporary Bulgarians and in early medieval population from SMC (Saltovo Mayaky Culture).

The existence of Chalcolithic-Iran (Hajj-Fruz) and Wusun related ancestral component in contemporary Bulgarians comes as a surprise and sheds light on both migration route and ethnic origins of Proto-Bulgarians. We interpret these results as an evidence for a Central –Asian connection for the tribes, constituting the population of SMC and Kubrat’s Old Great Bulgaria in Pontic steppe from 6th-7th century AD.

We identify Central Asian Wusun tribes as carriers of this component on the base from the results from f3 and f4 statistics. We suggest that Wusun-related tribes must have played role (or might have even been the backbone) in what became known as the Hunnic migration to Europe during 3rd-5th century AD. Same population must have taken part in the formation of the SMC (Saltovo-Mayaki Culture) and Great Old Bulgarian during 6th-9th century AD in Pontic – Caspian steppe.

We also explore the genomic origins of Thracians and their relations to contemporary Europeans. We conclude that contemporary Bulgarians do not harbor Thracian-specific ancestry, since ancient Thracian samples share more SNPs with contemporary Greeks and even contemporary Icelanders than with contemporary Bulgarians.
Free energies of stalk formation in the lipidomics era
Authors: Poojari Chetan S. , Scherer Katharina C. , Hub Jochen S.
Published: June 2021

Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at near-atomic resolution. The new method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.
Evidence for the null hypothesis in functional magnetic resonance imaging using group-level Bayesian inference
Authors: Masharipov Ruslan , Nikolaev Yaroslav , Korotkov Alexander , Didur Michael , Cherednichenko Denis , Kireev Maxim
Published: June 2021

Classical null hypothesis significance testing is limited to the rejection of the point-null hypothesis; it does not allow the interpretation of non-significant results. Moreover, studies with a sufficiently large sample size will find statistically significant results even when the effect is negligible and may be considered practically equivalent to the ‘null effect’. This leads to a publication bias against the null hypothesis. There are two main approaches to assess ‘null effects’: shifting from the point-null to the interval-null hypothesis and considering the practical significance in the frequentist approach; using the Bayesian parameter inference based on posterior probabilities, or the Bayesian model inference based on Bayes factors. Herein, we discuss these statistical methods with particular focus on the application of the Bayesian parameter inference, as it is conceptually connected to both frequentist and Bayesian model inferences. Although Bayesian methods have been theoretically elaborated and implemented in commonly used neuroimaging software, they are not widely used for ‘null effect’ assessment. To demonstrate the advantages of using the Bayesian parameter inference, we compared it with classical null hypothesis significance testing for fMRI data group analysis. We also consider the problem of choosing a threshold for a practically significant effect and discuss possible applications of Bayesian parameter inference in fMRI studies. We argue that Bayesian inference, which directly provides evidence for both the null and alternative hypotheses, may be more intuitive and convenient for practical use than frequentist inference, which only provides evidence against the null hypothesis. Moreover, it may indicate that the obtained data are not sufficient to make a confident inference. Because interim analysis is easy to perform using Bayesian inference, one can evaluate the data as the sample size increases and decide to terminate the experiment if the obtained data are sufficient to make a confident inference. To facilitate the application of the Bayesian parameter inference to ‘null effect’ assessment, scripts with a simple GUI were developed.
Characterizing Hydrogen Bonds in Intact RNA from MS2 Bacteriophage Using Solid State Magic Angle Spinning NMR
Authors: Lusky Orr Simon , Meir Moran , Goldbourt Amir
Published: June 2021

Ribonucleic acid (RNA) is a polymer with pivotal functions in many biological processes. RNA structure determination is thus a vital step towards understanding its function. The secondary structure of RNA is stabilized by hydrogen bonds formed between nucleotide base pairs and it defines the positions and shapes of functional stem-loops, internal loops, bulges, and other functional and structural elements. In this work we present a methodology for studying large intact RNA biomolecules using homonuclear 15N solid state nuclear magnetic resonance (NMR) spectroscopy. We show that Proton Driven Spin Diffusion (PDSD) experiments with long mixing times, up to 16s, improved by the incorporation of multiple rotor-synchronous 1H inversion pulses (termed Radiofrequency Dipolar Recoupling, RFDR, pulses), reveal key hydrogen-bond contacts. In the full-length RNA isolated from MS2 phage, we observed strong and dominant contributions of G-C Watson-Crick base pairs, and beyond these common interactions, we observe a significant contribution of the G-U wobble base pairs. Moreover, we can differentiate base-paired and non-base-paired nitrogen atoms. Using the improved technique facilitates characterization of hydrogen-bond types in intact large-scale RNA using solid-state NMR. It can be highly useful to guide secondary structure prediction techniques, and possibly structure determination methods.
Using top-down modulation to optimally balance shared versus separated task representations
Authors: Verbeke Pieter , Verguts Tom
Published: June 2021

Human adaptive behavior requires continually learning and performing a wide variety of tasks, often with very little practice. To accomplish this, it is crucial to separate neural representations of different tasks in order to avoid interference. At the same time, sharing neural representations supports generalization and allows faster learning. Therefore, a crucial challenge is to find an optimal balance between shared versus separated representations. Typically, models of human cognition employ top- down modulatory signals to separate task representations, but there exist surprisingly little systematic computational investigations of how such modulation is best implemented. We identify and systematically evaluate two crucial features of modulatory signals. First, top-down input can be processed in an additive or multiplicative manner. Second, the modulatory signals can be adaptive (learned) or non-adaptive (random). We cross these two features, resulting in four modulation networks which are tested on a variety of input datasets and tasks with different degrees of stimulus-action mapping overlap. The multiplicative adaptive modulation network outperforms all other networks in terms of accuracy. Moreover, this network develops hidden units that optimally share representations between tasks. Specifically, different than the binary approach of currently popular latent state models, it exploits partial overlap between tasks.
Colocalized, Bidirectional Optogenetic Modulations in Freely Behaving Mice with a Wireless Dual-Color Optoelectronic Probe
Authors: Li Lizhu , Lu Lihui , Ren Yuqi , Tang Guo , Zhao Yu , Cai Xue , Shi Zhao , Ding He , Liu Changbo , Cheng Dali , Xie Yang , Wang Huachun , Fu Xin , Yin Lan , Luo Minmin , Sheng Xing
Published: June 2021

The precise control of neural activities at both cellular and circuit levels reveals significant impacts on the fundamental neuroscience explorations and medical applications. Optogenetic methods provide efficient cell-specific modulations, and the ability of simultaneous neural activation and inhibition in the same brain region of freely moving animals is highly desirable and being actively researched. Here we report bidirectional neuronal activity manipulation accomplished by a wireless, dual-color optogenetic probe in synergy with the co-expression of two spectrally distinct opsins (ChrimsonR and stGtACR2) in a rodent model. Based on vertically assembled, thin-film microscale light-emitting diodes (micro-LEDs) with a lateral dimension of 125 × 180 µm2 on flexible substrates, the dual-color probe shows colocalized red and blue emissions and allows chronic in vivo operations with desirable biocompatibilities. In addition, we discover that neurons co-expressing the two opsins can be deterministically evoked or silenced under red or blue irradiations. Implanted in behaving mice, the wirelessly controlled dual-color probe interferes with dopaminergic neurons in the ventral tegmental area (VTA), increasing or decreasing dopamine levels with colocalized red and blue stimulations. Such bidirectional regulations further generate rewarding and aversive behaviors of freely moving mice in a place preference test and interrogate social interactions among multiple mice. The technologies established here will create numerous opportunities and profound implications for brain research.
Symbiosis increases population size and buffers environmental fluctuations in a physiologically-structured model parameterized for thyasirid bivalves
Authors: Mariño Joany , Dufour Suzanne C. , Hurford Amy
Published: June 2021

Symbioses whereby one partner provisions a nutritional resource to the other may alter energy allocation towards reproduction and survival in the recipient partner, potentially impacting population dynamics. Asymbiotic thyasirid bivalves feed predominantly on free-living bacteria, which fluctuate in abundance due to seasonality-driven temperature variations. Symbiotic thyasirids are mixotrophs, gaining nutrients from free-living bacteria and symbiotic bacteria that they host on their enlarged gills. Symbiotic bacteria may function as an additional energy reserve for thyasirids, allowing the hosts to allocate more energy to reproduction. We hypothesize that, for symbiotic thyasirids, the symbionts are a nutritional source that mitigates resource limitation. Using Dynamic Energy Budget theory, we built a physiologically-structured population model assuming equal mortality rates in both species. We find that without seasonal fluctuations, symbiotic thyasirids have higher abundances than asymbiotic thyasirids since the symbionts increase reproduction. Both species have similar population sizes in fluctuating environments, suggesting different adaptations to seasonality: asymbiotic thyasirids have adapted their physiology, while symbiotic thyasirids have adapted through mixotrophy. Our results highlight the significance of linking individual energetics and life-history traits to population dynamics and are the first step to-wards understanding the role of symbioses in population and community dynamics.
Celebrating a decade ofInternational Journal of Lean Six Sigma– a bibliometric analysis to uncover the “as is” and “to be” states
Authors: Puram Praveen , Gurumurthy Anand
Published: June 2021

Purpose

International Journal of Lean Six Sigma(IJLSS) has completed a decade. To celebrate the same, this study aims to review the articles published in IJLSS from its inception to the year 2020. The journal’s trends and professional impact over the years are investigated and potential future research directions are proposed.

Design/methodology/approach

A bibliometric analysis comprising of citation, co-citation and keyword co-occurrence methods is used on all the articles published in IJLSS till the year 2020. Content analysis is further done to analyse the type of research, type of industry studied and the articles’ target audience.

Findings

The journal has improved its reputation, productivity and impact over the years. Currently, studies published in IJLSS have been cited more than 5,000 times, with the most prominent themes being Six Sigma, Lean Six Sigma (LSS) and Lean in manufacturing and services. Researchers from India, the USA and the UK have contributed a significant number of publications. Most of the work published is case-based. There is a need for more empirical or survey-based research having high generalizability. Future studies should also focus on integrating LSS with emerging topics such as sustainability, Industry 4.0 and the like.

Research limitations/implications

The study provides evidence of the impact of IJLSS and highlights the trend in the domain of LSS. It can be of use for the editorial board members to identify potential areas to focus on in the future. Researchers can use it to further their research by working on the research gaps identified.

Originality/value

This paper is the first to trace the progress of IJLSS from its inception till the year 2020.