bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic Review and Meta-analysis of Rate of Major Amputation Following Endovascular Intervention in Chronic Limb-Threatening Ischaemia
Authors: Bergman Henry I , Elghazaly Hussein , Thapar Ankur , Davies Alun H.
Published: December 2022

Background

Despite significant improvements in endovascular technology and anaesthetic practice over the last 20 years, patients with CLTI remain at high risk of major limb amputation and overall mortality. The aim of this systematic review was to provide a contemporary review of the rate of major amputation and key clinical outcomes following all endovascular interventions in CLTI.

Methods

A systematic review and meta-analysis of prospective studies from 2010-2020 reporting the risk of major lower limb amputation in patients with CLTI. MEDLINE, EMBASE, the Cochrane Database for Systematic Reviews andClinicalTrials.govwere searched for relevant studies by 2 reviewers. The primary endpoint was rate of major limb amputation at 1 year and 2 years. Meta-analysis of proportions was employed using the random effects model. Studies were quality assessed using the ROBINS-I tool. To investigate factors associated with major limb amputations, subgroup analyses and meta-regression for clinical-demographic and lesion characteristics were employed.

Results

A total of 28 studies, from 24 manuscripts were eligible for inclusion. These included a total of 49,756 patients. At one-year post-revascularisation, the pooled rate of major lower limb amputations at 1 year was 8.6% (95% CI 6.7% - 11.0%). At two years, the rate of major amputations was 11.1% (95% CI 7.6% - 16.0%). Subgroup analysis showed that in studies that mandated stent deployment for all patients, there was a significantly lower rate of major amputations of 5.1% (95% CI 4.7% - 5.5%). Meta-regression showed that none of the clinical-demographic and lesion characteristics were associated with major lower limb amputations, and no volume-outcome relationship was observed.

Conclusions

This review provides important benchmarking information on the outcomes of endovascular intervention in a frail CLTI cohort. This provides a realistic evaluation of risk to facilitate full informed consent and the setting of realistic expectations regarding the need for reintervention, major and minor amputation and overall mortality.
Treatment Success and associated factors among patients with Pulmonary Tuberculosis attending Kampala Capital City Authority health facilities: A retrospective cohort study
Authors: Tumusiime Cathbert , Katamba Achilles , Nakiyingi Lydia , Kalyango Joan
Published: December 2022

Background

TB treatment success remains low in Uganda at 82%, below the recommended WHO target (≥90%). Consequences of poor treatment outcome include; increased MDR-TB prevalence, treatment costs and death. Kampala Capital City Authority (KCCA) public health facilities are congested which compromises the care given to pulmonary tuberculosis patients (PTB) that affects the treatment success of patients. However, there is scarce information regarding factors that are associated with treatment success among PTB patients in KCCA public health facilities.

General Objective

To determine the treatment success and associated factors among patients with pulmonary tuberculosis attending KCCA public health facilities in Kampala between July 2019 and June 2020.

Methods

A retrospective cohort study that involved review of records for 772 PTB patients who were enrolled on TB treatment in five KCCA health facilities from July 2019 to June 2020. Data on socio-demographic and clinical factors was abstracted from health facility TB registers. Data was entered in epidata and analyzed using STATA_v14 software. A modified poison regression model with robust standard errors was used in analysis and risk ratios were reported.

Results

Treatment success was 87.2% (CI: 84.2%-89.1%), PTB patients who cured accounted for 413 (53.5%) and 260 (33.7%) completed treatment. Factors associated with PTB treatment success were: being classified as a clinically diagnosed PTB patients (aRR= 0.8, CI: 0.53 - 0.94, P value =0.021) and having a positive HIV/AIDS status (aRR= 0.7, CI: 0.43 - 0.88, P value =0.006) reduced treatment success and having a community volunteer as a treatment supporter was associated with increased treatment success (aRR= 1.2, CI: 1.06 - 3.28, P value =0.028).

Conclusion

Over 80% of PTB patients in KCCA public health facilities achieve treatment success although this is still below the WHO target. Factors associated with TB treatment success include; being classified as a clinically diagnosed PTB patient, having a positive HIV/AIDS status as factors that reduce treatment success and having a community volunteer as a treatment supporter improves treatment success. Efforts such as consistent follow-ups should be encouraged among clinically diagnosed and HIV/AIDS positive PTB patients. Additionally, community volunteers should be empowered to support PTB patients.
Coronary vessel assembly involves patterned endocardial sprouting and tip-cell-to artery specification
Authors: Cano Elena , Paech Jennifer , Kanda Masatoshi , Lindberg Eric L. , Hollfinger Irene , Brauening Caroline , Fischer Cornelius , Hübner Norbert , Gerhardt Holger
Published: December 2022

The coronary vasculature comprises superficial coronary veins and deeper coronary arteries and capillaries that critically support the high metabolic activity of the beating heart. Understanding how different endothelial progenitor sources jointly shape and remodel the coronary vasculature into its adult pattern has recently attracted great research interest, and spurred much debate. Here, using lineage tracing tools in combination with three-dimensional imaging, live-imaging in explants and single-cell transcriptional profiling, we demonstrate that sprouting angiogenesis drives both sinus venosus and endocardial contribution to coronary plexus. Whereas previous studies limit endocardial contribution to coronary vessels to the interventricular septum and ventral aspect of the heart, our study demonstrates extensive endocardial sprouting angiogenesis in the free ventricular walls. In particular, we identify a distinct subpopulation of endocardial cells that express future coronary markers and reside in both the embryonic and adult ventricular wall endocardium. Most importantly, we provide evidence for sprouting angiogenesis from both endocardium and subepicardial plexus towards the inner myocardial wall to determine pre-arterial specification. Additionally, sprouting from the endocardium leads to the establishment of perfused connections to the advancing coronary plexus, also followed by transitioning to the pre-arterial cell state. Distinct molecular profiles characterize sprouting populations in the intramyocardial and subepicardial layers that shape the prospective coronary arteries and veins, respectively. Harnessing the endocardial progenitors and targeting the distinct sprouting populations may in the future serve to tailor cardiac vascular adaptations for therapeutic purposes.
Discovery and molecular basis of chloride as an allosteric activator and catalytic inhibitor for Class-D β-lactamases
Authors: Zhou Qi , Catalán Pablo , Bell Helen , Baumann Patrick , Evans Rhodri , Yang Jianhua , Zhang Zhen , Zappalà Davide , Zhang Ye , Blackburn George Michael , He Yuan , Jin Yi
Published: December 2022

Oxacillinase (OXA)-48-like carbapenemases are epidemic class D β-lactamases inEnterobacterales, resulting in high mortality. Though the chemical mechanism has been clearly established, for decades, the link between the biphasic kinetic behaviour of these enzymes, which significantly impacts antibiotic efficacy, and the state of carbamylated lysine has been elusive. Here, substitutingN-carbamylated lysine73 with a chemically-stableN-acetyl lysine allows us to prove the origin of catalytic inhibition is not decarbamylation and enables us to capture an unprecedented inactive acyl-intermediate wedged in place by a chloride ion against the conserved residue arginine250. We here identify chloride as a “Janus effector” acting by allosteric activation of the burst phase and inhibition of the steady-state for a series of β-lactam substrates in kinetic assays. Chloride ions are necessarily present in both laboratory and clinical OXA activity assays and their inseparable role is now identified. Our finding suggests a new direction for the discovery of next-generation antibiotics specific for β-lactamases of Class D.
Proximity-dependent recruitment of Polycomb Repressive Complexes by the lncRNAAirn
Authors: Braceros Aki K. , Schertzer Megan D. , Omer Arina , Trotman Jackson B. , Davis Eric S. , Dowen Jill M. , Phanstiel Douglas H. , Aiden Erez Lieberman , Calabrese J. Mauro
Published: December 2022

During mouse embryogenesis, expression of the lncRNAAirninduces gene silencing and recruits Polycomb Repressive Complexes (PRCs) to varying extents over a 15 megabase domain. The mechanisms remain unclear. Using high-resolution approaches, we show in mouse trophoblast stem cells thatAirnexpression induces long-range changes to chromatin architecture that coincide with PRC-directed modifications and center around CpG island promoters that contact theAirnlocus even in the absence ofAirnexpression. Intensity of contact betweenAirnlncRNA and target chromatin correlated with underlying intensity of PRC-directed chromatin modifications. Deletion of CpG islands that form contacts withAirnaltered long-distance silencing and PRC activity in a manner that correlated with changes in chromatin architecture. We conclude thatAirnis a potentcis-acting lncRNA whose primary functions of transcriptional repression and PRC recruitment are controlled by an equilibratory network of DNA regulatory elements that modulate its frequency of contact with target chromatin.
Acquired and intrinsic resistance to vemurafenib in BRAFV600E-driven melanoma brain metastases
Authors: Zhang Ping , Kuil Laura E. , Buil Levi C.M. , Freriks Stephan , Beijnen Jos H. , van Tellingen Olaf , de Gooijer Mark C.
Published: December 2022

Purpose

BRAFV600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We here tested the hypothesis that the drug efflux transporters P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) expressed at the blood–brain barrier (BBB) offer MBMs protection from therapy.

Methods

We intracranially implanted A375 tumor cells in wild-type andAbcb1a/b;Abcg2-/-mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib administration and determined the efficacy against brain metastases and subcutaneous lesions.

Results

Although contrast-enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs inAbcb1a/b;Abcg2-/-mice compared to wild-type mice. Concordantly, P-gp and BCRP are expressed in MBM-associated brain endothelium both in patients and in A375 xenografts and limited vemurafenib penetration into A375 MBMs. Confirming the BBB-specific context of this protection, vemurafenib was equally effective against subcutaneous A375 tumors in WT andAbcb1a/b;Abcg2-/-mice. Intriguingly, although initially responsive, A375 MBMs rapidly developed therapy resistance, even inAbcb1a/b;Abcg2-/-mice, and this was unrelated to pharmacokinetic or target inhibition issues. Rather, MBMs likely resorted to noncanonical growth signaling, as target inhibition of canonical MAPK pathway signaling components was maintained in resistant intracranial A375 tumors.

Conclusions

We demonstrate that BRAFV600E-driven MBMs are partly intrinsically protected from vemurafenib by the BBB. Intriguingly, MBMs can also rapidly acquire resistancein situ, likely by resorting to non-canonical growth signaling.
Leveraging a Billion-Edge Knowledge Graph for Drug Re-purposing and Target Prioritization using Genomically-Informed Subgraphs
Authors: Martin Brian , Jacob Howard J. , Hajduk Philip , Wolfe Elaine , Chen Loren , Crosby Henry , Lefever Matthew , Wendell Richard
Published: December 2022

Drug development is a resource and time-intensive process resulting in attrition rates of up to 90%. As a result, repurposing existing drugs with established safety and pharmacokinetic profiles is gaining traction as a way of accelerating therapeutics development. Here we have developed unique machine learning-driven Natural Language Processing and biomedical semantic technologies that mine over 53 million biomedical documents to automate the generation of a 911M edge knowledge graph. We then applied subgraph queries that relate drugs to diseases using genetic evidence to identify potential drug repurposing candidates for a broad range of diseases. We use Carney Complex, a disease with no known treatment, to illustrate our approach. This analysis revealed Ruxolitinib (Incyte, trade name Jakafi), a JAK1/2 inhibitor with an established safety and efficacy profile approved to treat myelofibrosis, as a potential candidate for the treatment of Carney Complex through off-target drug activity.
MODELING POLARITY SITE MOVEMENT IN YEAST VIA CALCIUM-MEDIATED REGULATION OF GAP ACTIVITY
Authors: Parikh Vatsal
Published: December 2022

Symmetry-breaking polarization is a process that occurs in many cells. In budding yeast cells specifically, this polarization is possible due to the presence of a positive feedback loop, which allows for one and only one front to develop. Furthermore, in mating yeast cells the detection of pheromones plays a crucial role in the cell’s development of a polarity site; however, due to the microscopic size of yeast cells, there is often error in the initial polarity site’s accuracy. As a result, yeast cells can correct their polarity site by allowing the GTP-Cdc42 cluster to “wander”. This is typically considered as the indecisive phase of a cell. Recent studies have identified that cytosolic Ca2+bursts, caused by sexual pheromones, increase the activity of GTPase-activating protein (GAP). This project tests this from a modeling perspective by adding a module of code to an already established positive feedback model that allows periodic spikes of GAP activity to occur. The model was successfully able to simulate the effects of calcium-mediated GAP spikes by portraying oscillating polarity sites and “wandering” polarity sites, using specific parameters based on biochemical data.
Benchmarking single-cell hashtag oligo demultiplexing methods
Authors: Howitt George , Feng Yuzhou , Tobar Lucas , Vassiliadis Dane , Hickey Peter , Dawson Mark A. , Ranganathan Sarath , Shanthikumar Shivanthan , Neeland Melanie , Maksimovic Jovana , Oshlack Alicia
Published: December 2022

Sample multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells’ RNA to determine their sample of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to samples. In this study, we critically assess the performance of seven HTO demultiplexing tools:hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFFandHashSolo. The comparison uses data sets where each sample has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic “ground truth”. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal counts distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in a scRNA-seq experiment.
Multimodal learning of noncoding variant effects using genome sequence and chromatin structure
Authors: Tan Wuwei , Shen Yang
Published: December 2022

Motivation

A growing amount of noncoding genetic variants, including single-nucleotide polymorphisms (SNPs), are found to be associated with complex human traits and diseases. Their mechanistic interpretation is relatively limited and can use the help from computational prediction of their effects on epigenetic profiles. However, current models often focus on local, 1D genome sequence determinants and disregard global, 3D chromatin structure that critically affects epigenetic events.

Results

We find that noncoding variants of unexpected high similarity in epigenetic profiles, with regards to their relatively low similarity in local sequences, can be largely attributed to their proximity in chromatin structure. Accordingly we have developed a multimodal deep learning scheme that incorporates both data of 1D genome sequence and 3D chromatin structure for predicting noncoding variant effects. Specifically, we have integrated convolutional and recurrent neural networks for sequence embedding and graph neural networks for structure embedding despite the resolution gap between the two types of data, while utilizing recent DNA language models. Numerical results show that our models outperform competing sequence-only models in predicting epigenetic profiles and their use of long-range interactions complement sequence-only models in extracting regulatory motifs. They prove to be excellent predictors for noncoding variant effects in gene expression and pathogenicity, whether in unsupervised “zero-shot” learning or supervised “few-shot” learning.

Availability

Codes and data access can be found athttps://github.com/Shen-Lab/ncVarPred-1D3D

Contact

yshen@tamu.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Bacillus subtilisencodes a discrete flap endonuclease that cleaves RNA-DNA hybrids
Authors: Lowder Frances Caroline , Simmons Lyle A.
Published: December 2022

Current models for Okazaki fragment maturation in eubacteria invoke RNA cleavage by RNase H, followed by strand displacement synthesis and 5′ RNA flap removal by DNA polymerase I (Pol I). RNA removal by Pol I is thought to occur through the 5′-3′ flapendo/exonuclease (FEN) domain, located in the N-terminus of the protein. In addition to Pol I, many bacteria encode a second, Pol I-independent FEN. The contribution of Pol I and Pol I-independent FENs to DNA replication and genome stability remains unclear. In this work we purified Pol I and FEN, then assayed these proteins on a variety of RNA-DNA hybrid and DNA-only substrates. We found that FEN is far more active than Pol I on 5′ flapped and nicked RNA-DNA hybrid substrates. We found that the 5′ nuclease activity ofB. subtilisPol I is feeble, even during DNA synthesis when a 5′ flapped substrate is formed modeling an Okazaki fragment intermediate. Examination of Pol I and FEN on DNA-only substrates shows that FEN is more active than Pol I on most substrates tested. Further experiments show that ΔpolAphenotypes are completely rescued by expressing the C-terminal polymerase domain while expression of the N-terminal 5′ nuclease domain fails to complement ΔpolA. Cells lacking FEN (ΔfenA) show a phenotype in conjunction with an RNase HIII defect, providing genetic evidence for the involvement of FEN in Okazaki fragment processing. With these results, we propose a model where cells remove RNA primers using FEN while upstream Okazaki fragments are extended through synthesis by Pol I. Our model is similar to models for Okazaki fragment processing in eukaryotes, where Pol d catalyzes strand displacement synthesis followed by 5′ flap cleavage using FEN-1.

Author Summary

5′ flap endo/exonuclease (FEN) activity provides an essential contribution to DNA replication and repair in all cellular life. In bacteria, DNA polymerase I is thought to be the central enzyme involved in Okazaki fragment processing, using its DNA polymerase and 5′ nuclease activities to generate and then remove the 5’ ssRNA segment of an Okazaki fragment. Many bacterial genomes encode a second, discrete FEN in addition to Pol I. We show that FEN is the primary 5′ nuclease used byB. subtilisfor primer removal. FEN activity exceeds that of Pol I on most substrates, including several that mimic Okazaki fragment intermediates. Additionally, we provide genetic evidence showing that FEN is involved in Okazaki fragment processing and that it is the DNA polymerase domain of Pol I rather than its 5′ nuclease domain that is importantin vivo. With our results, we propose a new model for Okazaki fragment processing inB. subtilis, which may be prevalent in a wider group of bacteria.
Single-centre, non-randomised clinical trial at a tertiary care centre to investigate 1-year changes in social experiences and biomarkers of well-being after bariatric surgery in individuals with severe obesity: protocol for the Bariatric Surgery and Social Experiences (BaSES) study
Authors: Pfabigan Daniela M. , Hertel Jens K. , Svanevik Marius , Lindberg Morten , Sailer Uta , Hjelmesæth Jøran
Published: December 2022

Abstract

Introduction

Obesity is linked to increased loneliness and less enjoyment of social interactions. While bariatric surgery is the most effective treatment targeting severe obesity, there is limited understanding as to whether patients experience social interactions differently after surgery. The Bariatric Surgery and Social Experiences Study (BaSES) is designed to assess potential changes in how much patients enjoy and engage in daily social interactions 1 year after Roux- en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG).

Methods and analysis

Single-centre, non-randomised clinical trial carried out at the Department of Endocrinology, Obesity and Nutrition at Vestfold Hospital Trust, Norway. Eligible patients (N=113) will undergo either RYGB, SG or single anastomosis sleeve ileal bypass (SASI). The primary outcome measure is change in the social experience score (assessed with a questionnaire) from a pre-surgery to a follow-up assessment 1 year after RYGB and SG. The respective changes after SASI will be assessed and considered exploratory.

Ethics and dissemination

The most recent protocol version of this study was reviewed and approved by the Regional Committee for Medical Research Ethics South East Norway (REK sør-øst A) on the 29thof August 2022 (ref: 238406). The results will be disseminated to academic and health professional audiences and the public via publications in international peer-reviewed journals and conferences.

Trial registration number

NCT05207917 (ClinicalTrials.gov)

Article Summary

Strengths and limitations of this study

The primary outcome (frequency and quality of social interactions) is assessed over a 14-days period per measurement timepoint to comprehensibly capture daily variation.

Multiple clinically relevant secondary outcomes including hair cortisol, endocannabinoid, and fasting ghrelin concentrations, cardiovascular risk factors and health-related and psychological patient-reported-outcomes are assessed.

The sample size is limited and thus may not provide sufficient statistical power to compare the effects of RYGB and SG on secondary outcomes.
Out of Pocket Spending on Insulin under $35 Copayment Caps
Authors: Bakkila Baylee F. , Basu Sanjay , Lipska Kasia J.
Published: December 2022

The high cost of insulin has made it inaccessible to many patients who need it. The Inflation Reduction Act (IRA), which was recently signed into law, limits out of pocket (OOP) spending on insulin to $35 for a 30-day supply for individuals covered by Medicare. In this study, we estimate substantial OOP savings for individuals who require insulin, finding that Medicare-insured persons are projected to save nearly one-fifth of their expenditures on insulin.
It’s complicated…: Exploring the missed opportunities and reasons for non-performance of assisted vaginal births in Kenya
Authors: Dickinson Fiona M , Allott Helen , Nyongesa Paul , Eyinde Martin , Muchemi Onesmus M , Karangau Stephen W , Ogoti Evans , Shaban Nassir A , Godia Pamela , Nyaga Lucy , Ameh Charles A
Published: December 2022

Unnecessary Caesarean Section (CS) can have adverse effects on women and their newborn. Assisted vaginal birth/delivery (AVB/AVD) using a suction device or obstetric forceps is a potential alternative when delays or complications occur in the second stage of labour. Unlike CS, AVB using a suction device does not require regional or general anaesthesia, can often be performed by midwives, and does not scar the uterus, lowering the risk of maternal mortality and morbidity, in this and subsequent pregnancies. This study examined the justification for, and outcomes of second stage CS (SSCS) and reasons for low levels of use of AVB, in Kenya.

Using a mixed methods study design, we reviewed case-notes from women having AVB and second-stage CS births, and conducted key informant interviews with healthcare providers, from 8 purposively selected hospitals in Kenya. Randomly selected SSCS and all AVB case-notes were reviewed by a panel of four experienced obstetricians, and appropriateness of the procedure assessed. Semi-structured interviews were conducted and analysed using a thematic approach.

Review of 67 SSCS case-notes showed 10% might have been conducted as AVBs, with a further 58% unable to be classified due to inadequate/inconsistent record keeping or excessive delay following initial CS decision. Outcomes following SSCS showed perinatal mortality rate of 89.6/1,000 births, with 11% of infants and 9% of mothers experiencing complications. Non-referred cases of AVB showed good outcomes. Twenty interviews were conducted with obstetricians, medical officers and midwives. The findings explored the experience and confidence of healthcare providers in performing AVBs, and adequacy of the training they received. Key reasons for non-performance included lack of functioning equipment, lack of trained staff or their rotation to other departments.

Reasons for non-performance of AVB were complex and often multiple. Any solutions to these problems will need to address various local, regional and national issues.
CHC22 clathrin functions in the early secretory pathway by two-site interaction with SNX5 and p115
Authors: Greig Joshua , Bates George T. , Yin Daowen I. , Briant Kit , Simonetti Boris , Cullen Peter J. , Brodsky Frances M.
Published: December 2022

The two clathrin isoforms, CHC17 and CHC22, mediate separate intracellular transport routes. CHC17 performs endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, transports the glucose transporter GLUT4 from the endoplasmic-reticulum-to-Golgi intermediate compartment (ERGIC) directly to an intracellular GLUT4 storage compartment (GSC) from where GLUT4 can be mobilized to the plasma membrane by insulin. Here, the molecular determinants distinguishing CHC22 from CHC17 trafficking are defined. The C-terminal trimerization domain of CHC22 binds SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. In tandem, an isoform-specific patch in the CHC22 N-terminal domain separately mediates binding to p115. This dual mode of clathrin recruitment, involving interactions at both heavy chain termini, is required for CHC22 targeting to ERGIC membranes to mediate the Golgi bypass route for GLUT4 traffic. Interference with either interaction inhibits GLUT4 targeting to the GSC, defining a bipartite mechanism regulating a key pathway in human glucose metabolism.
Evolutionary stability of social interaction rules in collective decision-making
Authors: Sigalou Anna , Mann Richard P.
Published: December 2022

Abstract

Social animals can use the choices made by other members of their groups as cues in decision making. Individuals must balance the private information they receive from their own sensory cues with the social information provided by observing what others have chosen. These two cues can be integrated using decision making rules, which specify the probability to select one or other options based on the quality and quantity of social and non-social information. Previous empirical work has investigated which decision making rules can replicate the observable features of collective decision making, while other theoretical research has derived forms for decision making rules based on normative assumptions about how rational agents should respond to the available information. Here we explore the performance of one commonly used decision making rule in terms of the expected decision accuracy of individuals employing it. We show that parameters of this model which have typically been treated as independent variables in empirical model-fitting studies obey necessary relationships under the assumption that animals are evolutionarily optimised to their environment. We further investigate whether this decision making model is appropriate to all animal groups by testing its evolutionary stability to invasion by alternative strategies that use social information differently, and show that the likely evolutionary equilibrium of these strategies depends sensitively on the precise nature of group identity among the wider population of animals it is embedded within.
Establishment of Bovine Trophoblast Stem Cells
Authors: Wang Yinjuan , Yu Leqian , Li Jie , Zhu Linkai , Ming Hao , Arteaga Carlos Pinzon , Sun Hai-Xi , Wu Jun , Jiang Zongliang
Published: December 2022

Here we report that a chemical cocktail (LCDM: hLIF,CHIR99021,DiM andMiH) previously used for extended potential pluripotent stem cells enables the de novo derivation and long-term culture of bovine trophoblast stem cells (TSCs). Bovine TSCs exhibit transcriptomic and epigenetic features characteristic of trophectoderm cells from bovine embryos and retain developmental potency to differentiate into mature trophoblast cells.
PeptideForest: Semisupervised machine learning integrating multiple search engines for peptide identification
Authors: Ranff T. , Dennison M. , Bédorf J. , Schulze S. , Zinn N , Bantscheff M. , van Heugten J.J.R.M. , Fufezan C.
Published: December 2022

The first step in bottom-up proteomics is the assignment of measured fragmentation mass spectra to peptide sequences, also known as peptide spectrum matches. In recent years novel algorithms have pushed the assignment to new heights, unfortunately, different algorithms come with different strengths and weaknesses and choosing the appropriate algorithm poses a challenge for the user. Here we introduce PeptideForest, a semi-supervised machine learning approach that integrates the assignments of multiple algorithms to train a random forest classifier to elevate that issue. Additionally, PeptideForest increases the number of peptide-to-spectrum matches that exhibit a q-value lower than 1% by 25.2 ± 1.6% compared to MS-GF+ data on samples containing mixed HEK andE. coliproteomes. However, an increase in quantity does not necessarily reflect an increase in quality and this is why we devised a novel approach to determine the quality of the assigned spectra through TMT quantification of samples with known ground truths. Thereby, we could show that the increase in PSMs below 1% q-value does not come with a decrease in quantification quality and as such PeptideForest offers a possibility to gain deeper insights into bottom-up proteomics. PeptideForest has been integrated into our pipeline framework Ursgal and can therefore be combined with a wide array of algorithms.
A method for differential expression analysis and pseudo-temporal locating and ordering of genes in single-cell transcriptomic data
Authors: Zhang Bao , Zhang Hongbo
Published: December 2022

Identification of differentially expressed genes (DEGs) is a pivotal step in single-cell RNA sequencing (scRNA-seq) data analysis. The sparsity and multi-model distribution of scRNA-seq data decides that the traditional tools designed for bulk RNA-seq have several limitations when applied to single-cell data. On the other hand, tools specifically for DEGs analysis of scRNA-seq data normally does not consider the high dimensionality of the data. To this end, we present DEAPLOG, a method for differential expression analysis and pseudo-temporal locating and ordering of genes in single-cell transcriptomic data. We show that DEAPLOG has higher accurate and efficient in DEGs identification when compared with existing methods in both artificial and real datasets. Additionally, DEAPLOG can infer pseudo-time and embedding coordinates of genes, therefore is useful in identifying regulators in trajectory of cell fate decision.
The Mba1 homologue ofTrypanosoma bruceiis involved in the biogenesis of oxidative phosphorylation complexes
Authors: Wenger Christoph , Harsman Anke , Niemann Moritz , Oeljeklaus Silke , von Känel Corinne , Calderaro Salvatore , Warscheid Bettina , Schneider André
Published: December 2022

Consistent with other eukaryotes, theTrypanosoma bruceimitochondrial genome encodes mainly hydrophobic core subunits of the oxidative phosphorylation system. These proteins must be co-translationally inserted into the inner mitochondrial membrane and are synthesized by the highly divergent trypanosomal mitoribosomes, which have a much higher protein to RNA ratio than any other ribosome. Here, we show that the trypanosomal ortholog of the mitoribosome receptor Mba1 (TbMba1) is essential for normal growth of procyclic trypanosomes but redundant in the bloodstream form, which lacks an oxidative phosphorylation system. Proteomic analyses of TbMba1-depleted mitochondria from procyclic cells revealed reduced levels of many components of the oxidative phosphorylation system, most of which belong to the cytochrome c oxidase (Cox) complex, three subunits of which are mitochondrially encoded. However, the integrity of the mitoribosome and its interaction with the inner membrane were not affected. Pulldown experiments showed that TbMba1 forms a dynamic interaction network that includes the trypanosomal Mdm38/Letm1 ortholog and a trypanosome-specific factor that stabilizes the CoxI and CoxII mRNAs. In summary, our study suggests that the function of Mba1 in the biogenesis of membrane subunits of OXPHOS complexes is conserved among yeast, mammalian, and trypanosomes, which belong to two eukaryotic supergroups.
Prediction error drives associative olfactory learning and conditioned behavior in a spiking model ofDrosophila larva
Authors: Jürgensen Anna-Maria , Sakagiannis Panagiotis , Schleyer Michael , Gerber Bertram , Nawrot Martin Paul
Published: December 2022

Predicting reinforcement from the presence of environmental clues is an essential component of guiding goal-directed behavior. In insect brains, the mushroom body is central to learning the necessary associations between sensory signals and reinforcement. We propose a biologically realistic spiking network model of the Drosophila larva olfactory pathway for the association of odors and reinforcement to bias behavior towards approach or avoidance. We demonstrate that prediction error coding through the integration of currently present and expected reinforcement in dopaminergic neurons can serve as a driving force in learning that can, combined with a synaptic homeostasis mechanism, account for experimentally observed features of acquisition and loss of associations in the larva that depend on the intensity of odor and reinforcement and temporal features of their pairing. To allow direct comparisons of our simulations with behavioral data [1], we model learning-induced plasticity over the complete time course of behavioral experiments and simulate the locomotion of individual larvae towards or away from odor sources in a virtual environment.
BioNumPy: Fast and easy analysis of biological data with Python
Authors: Rand Knut , Grytten Ivar , Pavlovic Milena , Kanduri Chakravarthi , Sandve Geir Kjetil
Published: December 2022

Python is a popular and widespread programming language for scientific computing, in large part due to the powerfularray programminglibrary NumPy, which makes it easy to write clean, vectorized and efficient code for handling large datasets. A challenge with using array programming for biological data is that the data is often non-numeric and variable-length (such as DNA sequences), inhibiting out-of-the-box use of standard array programming techniques. Thus, a tradition in bioinformatics has been to use low-level languages like C and C++ to write efficient code. This makes the tools less transparent to the average computational biologist - making them harder to understand, modify and contribute to.

We here present a new Python package BioNumPy, which adds a layer on top of NumPy in order to enable intuitive array programming on biological datasets. BioNumPy is able to efficiently load biological datasets (e.g. FASTQ-files, BED-files and BAM-files) into NumPy-like data structures, so that NumPy operations like indexing, vectorized functions and reductions can be applied to the data. We show that BioNumPy is considerably faster than vanilla Python and other Python packages for common bioinformatics tasks, and in many cases as fast as tools written in C/C++. BioNumPy thus bridges a long-lasting gap in bioinformatics, allowing the same programming language (Python) to be used across the full spectrum from quick and simple scripts to computationally efficient processing of large-scale data.
THE REACTION TIME COSTS OF TRAJECTORY PLANNING
Authors: Feinstein Gil , Shkedy-Rabani Anat , Shmuelof Lior
Published: December 2022

Issuing a goal-directed action requires specifying the goal of the action as well as planning the hand trajectory to obtain it. Accumulating results suggest that planning a straight point-to-point trajectory is more efficient and likely to involve simpler optimization process compared to the planning of trajectories with more complex shapes (e.g., curved trajectories). We sought to find evidence for the qualitative difference between the two planning modes through the investigation of reaction times (RT) in a pointing task performed with the wrist. In experiment 1, 18 subjects performed delayed straight and curved via-point reaching movements to arrays of 2 or 8 targets. Both trajectory type and number of possible targets affected RT. In experiment 2 (N=14), we demonstrate a switching cost between the issuing of the two types of trajectories, irrespective of changes in target position. Unexpectedly, trajectory type did not affect RT in experiment 2, likely due to the lack of target pre-cuing in experiment 2. Our results suggest that the planning of curved and straight trajectories differ in their memory load during pre-planning and requires a time-consuming update of the motor commands when switching between straight and curved plans.
Dysregulated cysteine metabolism leads to worsened liver pathology in diabetes-tuberculosis comorbid mice
Authors: Chaudhary Shweta , Pahwa Falak , Nanda Ranjan K.
Published: December 2022

Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB). Interestingly, DM is growing to pandemic proportions in TB endemic South-East Asian countries. DM-TB comorbidity induced pathophysiological changes warrants a better understanding to develop effective therapeutics. Tissue metabolomic profiling of streptozotocin (STZ) induced diabetic animals, infected withMycobacterium tuberculosisH37Rv, showed metabolic dysregulation in the lungs, liver, brain, kidney and thigh muscle. At 3 w.p.i., the tissue (lungs, spleen, liver) bacterial loads were similar between DM-TB and TB with worsened lung pathology. Enrichment analysis of the deregulated liver metabolites (n=20; log2DM-TB/TB>±1.0) showed major perturbation in the cysteine-methionine, glycine-serine, branched chain amino acid (BCAA) and fatty acid metabolism. Parallel relative quantification of liver proteome of DM-TB and control mice groups (TB, DM and healthy) identified 1833 proteins which showed group specific variations. Enrichment analysis of significantly altered proteins (n=60; log2DM-TB/TB>±1.0) showed major perturbations in cysteine-methionine metabolism corroborating the metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in DM-TB groups compared to controls. Furthermore, a global correlation analysis of liver metabolome and proteome data showed strong association between aspartic acid, pyruvic acid, leucine and isoleucine with Cyp450 enzymes (Cyp2a5, Cyp3a11, Cyp4a10, Cyp4a14) involved in retinol metabolism. Whereas iminodiacetic acid, isoleucine and γ-aminobutyric acid strongly correlated to enzymes (Cth, Ahcy, Kyat3, Mat1a) involved in the cysteine metabolism. So, targeting the perturbed liver cysteine and retinol metabolism in DM-TB comorbid condition might improve therapeutic outcomes and prevent organ damage.
Ion mobility mass spectrometry unveils global protein conformations in response to conditions that promote and reverse liquid-liquid phase separation
Authors: Robb Christina Glen , Dao Thuy P. , Ujma Jakub , Castañeda Carlos A. , Beveridge Rebecca
Published: December 2022

Liquid-liquid phase separation (LLPS) is a process by which biomacromolecules, particularly proteins, condense into a dense phase that resembles liquid droplets. Dysregulation of LLPS is implicated in disease, yet the relationship between protein conformational changes and LLPS remain difficult to discern. This is due to the high flexibility and disordered nature of many proteins that phase separate under physiological conditions, and their tendency to oligomerise. Here we demonstrate that ion mobility mass spectrometry (IM-MS) overcomes these limitations. We used IM-MS to investigate the conformational states of full-length ubiquilin-2 (UBQLN2) protein, LLPS of which is driven by high salt concentration and reversed by noncovalent interactions with ubiquitin (Ub). IM-MS revealed that UBQLN2 exists as a mixture of monomers and dimers, and that increasing salt concentration causes the UBQLN2 dimers to undergo a subtle shift towards extended conformations. UBQLN2 binds to Ub in 2:1 and 2:2 UBQLN2:Ub complexes which have compact geometries compared to free UBQLN2 dimers. Together, these results suggest that extended conformations of UBQLN2 are correlated with UBQLN2’s ability to phase separate. Overall, delineating protein conformations that are implicit in LLPS will greatly increase understanding of the phase separation process, both in normal cell physiology and disease states.
Molecular anatomy of eosinophil activation by IL5 and IL33
Authors: Mitchell Joshua M. , Mabin Justin W. , Muehlbauer Laura K. , Annis Douglas S. , Mathur Sameer K. , Johansson Mats W. , Hebert Alex S. , Fogerty Frances J. , Coon Joshua J. , Mosher Deane F.
Published: December 2022

IL5 and IL33 are major activating cytokines that cause circulating eosinophils to polarize, adhere, and release their granule contents. We correlated microscopic features of purified human blood eosinophils stimulated for 10 min with IL5 or IL33 with phosphoproteomic changes determined by multiplexed isobaric labeling. IL5 caused phosphorylation of sites implicated in JAK/STAT signaling and localization of pYSTAT3 to nuclear speckles whereas IL33 caused phosphorylation of sites implicated in NFκB signaling and localization of RELA to nuclear speckles. Phosphosites commonly impacted by IL5 and IL33 were involved in networks associated with cytoskeletal organization and eosinophil adhesion and migration. Many differentially regulated phosphosites were in a diverse set of large proteins—RAB44, a “large RAB” associated with crystalloid granules; NHSL2 and VIM that change localization along with the nucleus during polarization; TNFAIP3 vital for control of NFκB signaling, and SRRM2 and PML that localize, respectively, to nuclear speckles and PML bodies. Gene expression analysis demonstrated differential effects of IL5 and IL33 on IL18, CCL5, CSF1, and TNFSF14. Thus, common effects of IL5 and IL33 on the eosinophil phosphoproteome are important for positioning in tissues, degranulation, and initiation of new protein synthesis whereas specific effects on protein synthesis contribute to phenotypic heterogeneity.

KEY POINTS

IL33 and IL5 impact common pathways of eosinophil cytoskeletal reorganization, adhesion and migration.

Each lobe of the human eosinophil nucleus has a specific anatomy poised for new onset of cytokine-specific transcription and splicing.
Multiomic Analysis of Adult Diapause inDrosophila melanogasterIdentifies Hallmarks of Cellular Quiescence
Authors: Hutfilz Corinne
Published: December 2022

Age is a fundamental aspect of biology that underlies the efficacy of a broad range of functions. Identifying determinants for how quickly or slowly we age will contribute greatly to our understanding of age as a modifier of overall health, particularly to the advancement of therapeutic interventions designed to mitigate or delay age-associated disorders. While much work has been devoted to the study of genetic or pharmacological interventions that extend lifespan, this approach does not necessarily recapitulate the physiological profile of naturally long-lived individuals. Diapause and diapause-like states constitute natural, inducible and evolutionarily conserved examples of lifespan plasticity that are well-suited to serve as physiologically accurate models of longevity. Here, we leveraged a metabolically critical signaling organ in Drosophila, the fat body, to examine diapause-associated transcription in the context of chromatin accessibility and the regulation of lifespan. Through a combination of ATAC-seq and RNA-seq, our observations suggest chromatin is globally reorganized in diapause and may assume a poised conformation to facilitate the rapid transcription of pro-development genes upon diapause termination. We found particular significance of GAF, NELF, and RNA polymerase III in this context. Congruently, transcription during diapause appears to favor many processes supporting the maintenance of cellular quiescence and the inhibition of differentiation. Our data are consistent with a model wherein diapause induces cellular quiescence in the fat body, as was additionally supported through fluorescent microscopy and comparison with public ChIP-seq data for developmentally juvenile files. This work opens the possibility that longevity in diapause may be partially determined through a lack of mitogenic signaling from the quiescent niche, concurrent with changes to the hormonal and immunological profiles that skew metabolism towards tissue maintenance.
The miR156-targetedSlSBP15represses tomato shoot branching via modulating auxin transport and interacting withGOBLETandBRANCHED1b
Authors: Barrera-Rojas Carlos Hernán , Vicente Mateus Henrique , Pinheiro Brito Diego Armando , Silva Eder M. , Lopez Aitor Munoz , Ferigolo Leticia F. , do Carmo Rafael Monteiro , Silva Carolina M. S. , Silva Geraldo F.F. , Correa Joao P. O. , Notini Marcela M. , Freschi Luciano , Cubas Pilar , Nogueira Fabio T.S.
Published: December 2022

The microRNA156 (miR156)/SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE(SPL/SBP) regulatory hub is highly conserved among phylogenetically distinct species, but how it interconnects multiple pathways to converge to common integrators controlling shoot architecture is still unclear. Here, we demonstrated that the miR156/SlSBP15hub modulates tomato shoot branching (SB) by connecting phytohormones with important genetic pathways regulating both axillary bud (AB) development and outgrowth. We verified that plants overexpressing the miR156 (156-OE plants) display high SB, whereas plants overexpressing a miR156-resistant SlSBP15 alelle (rSBP15 plants) display arrested SB and are able to partially restore the wild-type (WT) phenotype in156-OE background. Although rSBP15 plants showed ABs smaller than MT, its activation is dependent on shoot apex-derived auxin transport inhibition. Additionally, hormonal measurements reveal that IAA and ABA concentrations were lower in 156-OE and higher in rSBP15-OE plants. SlSBP15 regulates AB development and outgrowth by inhibiting auxin transport and the activity ofGOBLET(GOB), and by interacting with BRANCHED1b (SlBRC1b) at the protein level to control abscisic acid (ABA) levels within ABs. Our data provide a new mechanism by which the miR156/SPL/SBPhub regulates SB, and suggest thatSlSBP15has potential applications in improving tomato architecture.