bluuebunny/crossref_metadata_2025 huggingface dataset:
Haptoglobin depletion during the first seven days of veno-venous ECMO therapy is associated with increased mortality and adverse outcomes in patients with ARDS
Authors: Bünger Victoria , Hunsicker Oliver , Krannich Alexander , Balzer Felix , Spies Claudia D. , Kuebler Wolfgang M. , Weber-Carstens Steffen , Menk Mario , Graw Jan A.
Published: April 2024

Background

Hemolysis is a frequent complication in patients with sepsis, ARDS, or extracorporeal membrane oxygenation (ECMO). Haptoglobin (Hp) can scavenge released cell-free hemoglobin (CFH). Hemolysis and low plasma concentrations of Hp may be independently associated with mortality in critically ill patients.

Methods

Retrospective analysis of 435 patients with ARDS and veno-venous ECMO therapy, admitted to a tertiary ARDS referral center (01/2007-12/2018). Hp-depletion was defined as decrease in plasma Hp concentration < 0.39 g/l within the first week after ECMO initiation. Patients with Hp depletion were compared to patients without Hp depletion. The primary endpoint was 28-day mortality. Secondary endpoints included organ dysfunction-free, renal replacement therapy (RRT)-free, vasopressor-free, and ECMO-free composites.

Results

Patients with Hp-depletion (n = 269) had a significantly higher mortality 28 days after ECMO initiation compared to patients without Hp-depletion (43.5%, [95% CI: 37.52-49.66] vs. 25.3%, [19.03-32.74], p < 0.001). Furthermore, patients with Hp depletion had fewer organ dysfunction-free days (subdistribution hazard ratio, [SHR] 0.35, [95% CI 0.25-0.50], p < 0.001), lower chances for successful weaning from renal replacement therapy (SHR 0.50, [0.32-0.79], p < 0.001), vasopressor therapy (SHR 0.39, [0.28-0.54], p < 0.001), and ECMO therapy (SHR 0.41, [0.30-0.57], p < 0.001) within 28 days after ECMO initiation. Patients with initial Hp <0.66 g/l had higher risks for Hp-depletion than patients with initial Hp ≥ 0.66 g/l.

Conclusion

Patients with Hp-depletion within the first week of ECMO therapy might benefit from close monitoring of hemolysis with early detection and elimination of the underlying cause. They might be potential candidates for future Hp supplementation therapy to prevent overload of the CFH-scavenger system.
BURNS INDUCE ALTERATIONS IN THE ACYL PROTEOME OF MICE AND HUMANS
Authors: Bieerkehazhi Shayahati , Barayan Dalia , Khalaf Fadi , de Brito Monteiro Lauar , Aijaz Ayesha , Volk Charlotte , Matveev Anna , Saldanha Sean , Faour Sara , Jeschke Marc G.
Published: April 2024

Hypermetabolic reprogramming triggered by thermal injury causes substantial morbidity and mortality. Despite the therapeutic potential of targeting this response, the underlying mechanisms remain poorly understood. Interestingly, protein S-acylation is a reversible posttranslational modification induced by metabolic alterations via DHHC acyltransferases. While this modification aids in the regulation of cellular functions, deregulated S-acylation contributes to various diseases by altering protein structure, stability, and localization. However, whether and how S-acylation may impact morbidity and mortality during postburn hypermetabolism is unknown. In this study, we discovered that alterations in the acyl proteome play a key role in mediating adverse outcomes that occur after burn injury. Using a murine model, we show that burn injury induces profound changes in the expression of various DHHC isoforms in metabolic organs central to regulating postburn hypermetabolism, the adipose tissue, and liver. This was accompanied by increased levels of S-acylated proteins in several pathways involved in mediating the adverse hypermetabolic response, including ER stress, lipolysis, and browning. In fact, similar results were also observed in adipose tissue from severely burned patients, as reflected by increased S-acylation of ERK1/2, eIF2a, ATGL, FGF21, and UCP1 relative to nonburn controls. Importantly, pharmacologically targeting this posttranslational modification using a nonselective DHHC inhibitor effectively attenuated burn-induced ER stress, lipolysis, and browning induction in an ex vivo explant model. Together, these findings suggest that S-acylation may facilitate the protein activation profile that drives burn-induced hypermetabolism and that targeting it could potentially be an effective strategy to restore metabolic function and improve outcomes after injury.
WTAP-MEDIATED M6A MODIFICATION OF KLF6 AGGRAVATES HYPOXIA/REOXYGENATION-INDUCED HUMAN CARDIOMYOCYTE INJURY
Authors: Fang Mingcheng , Li Ting , Wu Zhiyong
Published: April 2024

Background: Myocardial infarction (MI) is a severe condition that typically results from the ischemia and necrosis of heart muscle. Kruppel-like factor 6 (KLF6) can aggravate myocardial ischemia/reperfusion injury. This work aims to reveal its role and mechanism in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury. Methods: Human cardiomyocyte (AC16) was exposed to hypoxic treatment to mimic MI-like cell injury. mRNA expression levels of KLF6 and WT1-associated protein (WTAP) were detected by quantitative real-time polymerase chain reaction. Protein expression was detected by western blotting assay. Cell viability was assessed by CCK-8 assay. Cell apoptosis and cell cycle were investigated by flow cytometry. Enzyme-linked immunosorbent assays were conducted to detect IL-1β, TNF-α and IL-6 levels. Fe2+ colorimetric assay kit was used to detect Fe2+ level. MDA Content Assay Kit was used to detect MDA level. Cellular ROS Assay kit was applied to assess ROS level. The association of KLF6 and WTAP was identified by RNA immunoprecipitation assay and dual-luciferase reporter assay. Results: KLF6 and WTAP expression at mRNA and protein levels were significantly upregulated in serum samples of MI patients and H/R-induced AC16 cells when compared with control groups. KLF6 silencing attenuated H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress, and ferroptosis. Additionally, WTAP stabilized KLF6 mRNA by regulating its m6A modification. Furthermore, WTAP knockdown rescued H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress, and ferroptosis by decreasing KLF6 expression. Conclusion: WTAP-mediated m6A modification of KLF6 aggravated hypoxia/reoxygenation-induced apoptosis, inflammatory response, oxidative stress, and ferroptosis of human cardiomyocytes, providing a therapeutic strategy for MI.
Impact of Procedure Risk vs Frailty on Outcomes of Elderly Patients Undergoing Emergency General Surgery: Results of a National Analysis
Authors: Zakhary Bishoy , Coimbra Bruno C , Kwon Junsik , Allison-Aipa Timothy , Firek Matthew , Coimbra Raul
Published: April 2024

BACKGROUND:

The direct association between procedure risk and outcomes in elderly patients who undergo emergency general surgery (EGS) has not been analyzed. Studies only highlight the importance of frailty. A comprehensive analysis of relevant risk factors and their association with outcomes in elderly patients who undergo EGS is lacking. We hypothesized that procedure risk has a stronger association with relevant outcomes in elderly patients who undergo EGS compared with frailty.

STUDY DESIGN:

Elderly patients (age >65 years) undergoing EGS operative procedures were identified in the NSQIP database (2018 to 2020) and stratified based on the presence of frailty calculated by the Modified 5-Item Frailty Index (mFI-5; mFI 0 nonfrail, mFI 1 to 2 frail, and mFI ≥3 severely frail) and based on procedure risk. Multivariable regression models and receiving operative curve analysis were used to determine risk factors associated with outcomes.

RESULTS:

A total of 59,633 elderly patients who underwent EGS were classified into nonfrail (17,496; 29.3%), frail (39,588; 66.4%), and severely frail (2,549; 4.3%). There were 25,157 patients in the low-risk procedure group and 34,476 in the high-risk group. Frailty and procedure risk were associated with increased mortality, complications, failure to rescue, and readmissions. Differences in outcomes were greater when patients were stratified according to procedure risk compared with frailty stratification alone. Procedure risk had a stronger association with relevant outcomes in elderly patients who underwent EGS compared with frailty.

CONCLUSIONS:

Assessing frailty in the population of elderly patients who undergo EGS without adjusting for the type of procedure or procedure risk ultimately presents an incomplete representation of how frailty impacts patient-related outcomes.
Bifidobacterium apis sp. nov., isolated from the gut of honeybee (Apis mellifera)
Authors: Jiang Cheng-Shan , Li Chun Yan , Gu Chun Tao
Published: April 2024

A novel bifidobacterium (designated F753-1T) was isolated from the gut of honeybee (Apis mellifera). Strain F753-1T was characterized using a polyphasic taxonomic approach. Strain F753-1T was phylogenetically related to the type strains of Bifidobacterium mizhiensis, Bifidobacterium asteroides, Bifidobacterium choladohabitans, Bifidobacterium mellis, Bifidobacterium apousia and Bifidobacterium polysaccharolyticum, having 98.4–99.8 % 16S rRNA gene sequence similarities. The phylogenomic tree indicated that strain F753-1T was most closely related to the type strains of B. mellis and B. choladohabitans. Strain F753-1T had the highest average nucleotide identity (94.1–94.5 %) and digital DNA–DNA hybridization (56.3 %) values with B. mellis Bin7NT. Acid production from amygdalin, d-fructose, gentiobiose, d-mannose, maltose, sucrose and d-xylose, activity of α-galactosidase, pyruvate utilization and hydrolysis of hippurate could differentiate strain F753-1T from B. mellis CCUG 66113T and B. choladohabitans JCM 34586T. Based upon the data obtained in the present study, a novel species, Bifidobacterium apis sp. nov., is proposed, and the type strain is F753-1T (=CCTCC AB 2023227T=JCM 36562T=LMG 33388T).
biGMamAct: efficient CRISPR/Cas9-mediated docking of large functional DNA cargoes at theACTBlocus
Authors: Pelosse Martin , Marcia Marco
Published: April 2024

Recent advances in molecular and cell biology and imaging have unprecedentedly enabled multi-scale structure-functional studies of entire metabolic pathways from atomic to micrometer resolution, and the visualization of macromolecular complexesin situ, especially if these molecules are expressed with appropriately-engineered and easily-detectable tags. However, genome editing in eukaryotic cells is challenging when generating stable cell lines loaded with large DNA cargoes. To address this limitation, here, we have conceived biGMamAct, a system that allows the straightforward assembly of a multitude of genetic modules and their subsequent integration in the genome at theACTBlocus with high efficacy, through standardized cloning steps. Our technology encompasses a set of modular plasmids for mammalian expression, which can be efficiently docked into the genome in tandem with a validated Cas9/sgRNA pair through homologous-independent targeted insertion (HITI). As a proof of concept, we have generated a stable cell line loaded with an 18.3-kilobase-long DNA cargo to express 6 fluorescently-tagged proteins and simultaneously visualize 5 different subcellular compartments. Our protocol leads from thein-silicodesign to the genetic and functional characterization of single clones within 6 weeks and can be implemented by any researcher with familiarity with molecular biology and access to mammalian cell culturing infrastructure.
Modeling conditional distributions of neural and behavioral data with masked variational autoencoders
Authors: Schulz Auguste , Vetter Julius , Gao Richard , Morales Daniel , Lobato-Rios Victor , Ramdya Pavan , Gonçalves Pedro J. , Macke Jakob H.
Published: April 2024

Extracting the relationship between high-dimensional recordings of neural activity and complex behavior is a ubiquitous problem in systems neuroscience. Toward this goal, encoding and decoding models attempt to infer the conditional distribution of neural activity given behavior and vice versa, while dimensionality reduction techniques aim to extract interpretable low-dimensional representations. Variational autoencoders (VAEs) are flexible deep-learning models commonly used to infer low-dimensional embeddings of neural or behavioral data. However, it is challenging for VAEs to accurately model arbitrary conditional distributions, such as those encountered in neural encoding and decoding, and even more so simultaneously. Here, we present a VAE-based approach for accurately calculating such conditional distributions. We validate our approach on a task with known ground truth and demonstrate the applicability to high-dimensional behavioral time series by retrieving the conditional distributions over masked body parts of walking flies. Finally, we probabilistically decode motor trajectories from neural population activity in a monkey reach task and query the same VAE for the encoding distribution of neural activity given behavior. Our approach provides a unifying perspective on joint dimensionality reduction and learning conditional distributions of neural and behavioral data, which will allow for scaling common analyses in neuroscience to today's high-dimensional multi-modal datasets.
Information theory for data-driven model reduction in physics and biology
Authors: Schmitt Matthew S. , Koch-Janusz Maciej , Fruchart Michel , Seara Daniel S. , Rust Michael , Vitelli Vincenzo
Published: April 2024

Model reduction is the construction of simple yet predictive descriptions of the dynamics of many-body systems in terms of a few relevant variables. A prerequisite to model reduction is the identification of these relevant variables, a task for which no general method exists. Here, we develop a systematic approach based on the information bottleneck to identify the relevant variables, defined as those most predictive of the future. We elucidate analytically the relation between these relevant variables and the eigenfunctions of the transfer operator describing the dynamics. Further, we show that in the limit of high compression, the relevant variables are directly determined by the slowest-decaying eigenfunctions. Our information-based approach indicates when to optimally stop increasing the complexity of the reduced model. Furthermore, it provides a firm foundation to construct interpretable deep learning tools that perform model reduction. We illustrate how these tools work in practice by considering uncurated videos of atmospheric flows from which our algorithms automatically extract the dominant slow collective variables, as well as experimental videos of cyanobacteria colonies in which we discover an emergent synchronization order parameter.

Significance Statement

The first step to understand natural phenomena is to intuit which variables best describe them. An ambitious goal of artificial intelligence is to automate this process. Here, we develop a framework to identify these relevant variables directly from complex datasets. Very much like MP3 compression is about retaining information that matters most to the human ear, our approach is about keeping information that matters most to predict the future. We formalize this insight mathematically and systematically answer the question of when to stop increasing the complexity of minimal models. We illustrate how interpretable deep learning tools built on these ideas reveal emergent collective variables in settings ranging from satellite recordings of atmospheric fluid flows to experimental videos of cyanobacteria colonies.
Genome-wide profiling of highly similar paralogous genes using HiFi sequencing
Authors: Chen Xiao , Baker Daniel , Dolzhenko Egor , Devaney Joseph M , Noya Jessica , Berlyoung April S , Brandon Rhonda , Hruska Kathleen S , Lochovsky Lucas , Kruszka Paul , Newman Scott , Farrow Emily , Thiffault Isabelle , Pastinen Tomi , Kasperaviciute Dalia , Gilissen Christian , Vissers Lisenka , Hoischen Alexander , Berger Seth , Vilain Eric , Délot Emmanuèle ,   UCI Genomics Research to Elucidate the Genetics of Rare Diseases (UCI GREGoR) Consortium, Eberle Michael A
Published: April 2024

Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of a gene family. We applied Paraphase to 160 long (>10 kb) segmental duplication regions across the human genome with high (>99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 families with exceptionally low within-family diversity, where extensive gene conversion and unequal-crossing over have resulted in highly similar gene copies. Furthermore, our analysis of 36 trios identified 7de novoSNVs and 4de novogene conversion events, 2 of which are non-allelic. Finally, we summarized extensive genetic diversity in 9 medically relevant genes previously considered challenging to genotype. Paraphase provides a framework for resolving gene paralogs, enabling accurate testing in medically relevant genes and population-wide studies of previously inaccessible genes.
Sanger validation of WGS variants - when to?
Authors: Kopernik Arina , Zobkova Gaukhar , Doroschuk Natalia , Smirnova Anna , Molodtsova-Zolotukhina Daria , Sagaydak Olesya , Ryzhkova Oxana , Kutsev Sergey , Groznova Olga , Melikyan Lyusya , Bondarchuk Elizaveta , Woroncow Mary , Albert Eugene , Bogdanov Viktor , Volchkov Pavel
Published: April 2024

With the development of Next-Generation Sequencing (NGS) technologies it became possible to simultaneously analyze millions of variants. Despite the quality improvement it is generally still required to confirm the variants before reporting. However, in recent years the dominant idea is that one could define the quality thresholds for “high quality” variants which do not require orthogonal validation. Despite that, no works to date report the concordance between variants from whole genome sequencing and their gold-standard Sanger validation. In this study we analyzed the concordance for 1756 WGS variants in order to establish the appropriate thresholds for high-quality variants filtering. Resulting thresholds allowed us to drastically reduce the number of variants which require validation, to 5,6% and 1.2% of the initial set for caller-agnostic thresholds and caller-dependent QUAL threshold respectively.
Homeostatic Control on the Thought: a Comprehensive Explanation of Mind Wandering
Authors: Shinagawa Kazushi , Yamada Kota
Published: April 2024

Our thoughts are inherently dynamic, often wandering far from the current situation. Mind-wandering (MW), which is these thought transitions, is crucial for understanding the nature of human thought. Although previous research has identified various factors influencing MW, a comprehensive framework integrating these findings remains absent. Here, we propose that homeostasis has the potential to explain MW and validate the idea through simulations by replicating previous findings. We employed a homeostatic reinforcement learning model where independent drives for the task and others were assigned, and drive reduction became a reward and trained under sustained attention to the response task. We confirmed that the model behaves consistently with the empirical results reported in human experiments, suggesting that the model accurately captures the underlying mechanism of MW. Finally, we discuss the behavioral and neurobiological commonality between human thought and animal behavior and the possibility that the same principle, homeostasis, controls these phenomena.
TINNiK: Inference of the Tree of Blobs of a Species Network Under the Coalescent
Authors: Allman Elizabeth S. , Baños Hector , Mitchell Jonathan D. , Rhodes John A.
Published: April 2024

The tree of blobs of a species network shows only the tree-like aspects of relationships of taxa on a network, omitting information on network substructures where hybridization or other types of lateral transfer of genetic information occur. By isolating such regions of a network, inference of the tree of blobs can serve as a starting point for a more detailed investigation, or indicate the limit of what may be inferrable without additional assumptions. Building on our theoretical work on the identifiability of the tree of blobs from gene quartet distributions under the Network Multispecies Coalescent model, we develop an algorithm, TINNiK, for statistically consistent tree of blobs inference. We provide examples of its application to both simulated and empirical datasets, utilizing an implementation in theMSCquartets 2.0R package.

MSC Classification

92D15, 92D20
A unified theory for predicting pathogen mutual invasibility and co-circulation
Authors: Park Sang Woo , Cobey Sarah , E. Metcalf C. Jessica , Levine Jonathan M. , Grenfell Bryan T.
Published: April 2024

A key aim in the dynamics and control of infectious diseases is predicting competitive outcomes of pathogen interactions. Observed pathogen community structure indicates both considerable coexistence of related variants and spectacular instances of replacement, notably in seasonal influenza and SARS-CoV-2. However, an overall comparative quantitative framework for invasion and coexistence remains elusive. Inspired by modern ecological coexistence theory, we address this gap by developing pathogen invasion theory (PIT) and test the resulting framework against empirical systems. PIT predicts near-universal mutual invasibility across major pathogen systems, including seasonal influenza strains and SARS-CoV-2 variants. Predicting co-circulation from mutual invasibility further depends on the extent of overcompensatory susceptible depletion dynamics. Our analyses highlight the central role of immuno-epidemiological factors in determining pathogen coexistence and community structure.
Safety and long-term performance of the Medtronic 3830 lead in His-bundle vs. Left bundle branch area pacing: A single-center 5-year experience
Authors: Sarkar Abdullah , Sanchez-Nadales Alejandro , Sleiman Jose , Lewis-Camargo Antonio , Alonso Mileydis , Seijo Yelenis , Sanchez-Nadales Andres , Bibawy John , Helguera Marcelo , Pinski Sergio L. , Baez-Escudero Jose L.
Published: April 2024

BACKGROUND

The short-term safety, feasibility, and performance of the Medtronic SelectSecure 3830-69 cm pacing lead for conduction system pacing (CSP) has been reported; however, its longer-term performance is not well established.

OBJECTIVE

The purpose of this study is to examine the long-term performance of the 3830 lead for His Bundle Pacing (HBP) and Left Bundle Branch Area Pacing (LBBAP).

METHODS

We retrospectively reviewed all cases of CSP performed with the Medtronic SelectSecure 3830-69 cm pacing lead at Cleveland Clinic Florida between May 2016 and October 2021.

RESULTS

Of 515 attempts, HBP achieved an 85% success rate (340 cases), while LBBAP demonstrated a higher success rate of 97.4% (150 cases). The mean follow-up was 28 months for HBP and 14 months for LBBAP, with patient ages averaging 75 and 77 years, respectively. Only 7% of the cohort had an ejection fraction below 50%. The primary indications for HBP were sick sinus syndrome (35.5%), atrioventricular block (35.2%), cardiac resynchronization therapy (10%), and refractory atrial fibrillation (18.8%), with similar distributions for LBBAP. The HBP group’s capture threshold at implant was 1.3 ± 0.8 V at 0.8 ± 0.2 ms, which significantly increased at chronic follow-up to 1.68 ± 1.3 V at 0.7 ± 0.3 ms (p <0.001), whereas the LBBAP group’s capture threshold remained stable from 0.8 ± 0.5 V at 0.5 ± 0.3 ms to to 0.9 ± 0.5 V at 0.5 ± 0.3 ms, (p= 0.35). Lead revisions were more common in the HBP group (50 cases) than in the LBBAP group (5 cases), with exit block rates of 11.7% and 3%, respectively.

CONCLUSION

Using the 3830 lead for HBP can result in significantly elevated thresholds, loss of His-bundle capture, and frequent lead revision rates at long-term follow-up. These issues are less commonly seen when the lead is used for LBBAP.
Influence of Incorrect Documentation of Initial Cardiac Rhythm in Survivors of Out of Hospital Cardiac Arrest
Authors: Kumar Sant , Hockstein Max , Papolos Alexander I. , Devraj Mithun , Khalid Nauman , Lipinski Michael J. , Kenigsberg Benjamin B.
Published: April 2024

Background

In-hospital management of out-of-hospital cardiac arrest (OHCA) is heavily influenced by the initial rhythm (shockable vs. non-shockable). The prevalence of discordance between initial rhythm determination reported by emergency medical services (EMS) versus hospital teams is not well described. It is unclear whether such documentation discrepancies in OHCA influence inpatient clinical care including subsequent left heart catheterization (LHC). We hypothesized that discordance between EMS and hospital team documentation of OHCA initial rhythm was common and associated with differences in LHC frequency.

Methods

This was a retrospective, single-center study. OHCA patients from the Cardiac Arrest Registry to Enhance Survival (CARES) hospital database were linked by demographic and arrest history to OHCA patients identified by inpatient hospital billing codes from 2009 to 2017. Patients who expired within 24 hours of hospital presentation were excluded. Hospital documentation of OHCA initial rhythm and occurrence of LHC were manually reviewed. The relationship between EMS versus hospital team documentation of OHCA initial rhythm and occurrence of LHC were assessed by relative risk ratios with 95% confidence intervals.

Results

Out of 164 patients for analysis, 140 (85.4%) had concordant EMS and hospital documentation of OHCA initial rhythm. For OHCA with an EMS-documented shockable rhythm, the relative risk of LHC when hospital-documented concordant shockable vs. discordant non-shockable rhythm was 2.12 (95% RR CI: 0.76-5.93). For OHCA with an EMS-documented non-shockable rhythm, the relative risk of LHC when hospital-documented concordant non-shockable vs discordant shockable rhythm was 0.19 (95% CI: 0.05-0.69).

Conclusions

In patients with OHCA, discrepancy between EMS and hospital team documentation of the initial arrest rhythm is prevalent. This discrepancy may influence the incidence of LHC. Further research is needed to understand the clinical impact of discrepancies in rhythm communication between EMS and hospital teams.
Deviation from typical brain activity during naturalistic stimulation is related to personality traits
Authors: Jajcay Lucia , Tomeček David , Androvičová Renáta , Fajnerová Iveta , Děchtěrenko Filip , Rydlo Jan , Tintěra Jaroslav , Lukavský Jiří , Horáček Jiří , Hlinka Jaroslav
Published: April 2024

The relationship between personality and brain activity has been an increasingly popular topic of neuroscientific research. However, the limitations of both personality measures and neuroimaging, as well as methodological issues, continue to pose challenges to its understanding. The naturalistic viewing condition has been shown to enhance individual differences and might, therefore, be of benefit to the endeavor. Here, we thus examine this relationship using naturalistic fMRI of 82 healthy subjects. We implemented a simple dimensionality reduction method to characterize brain activity by its ‘typicality’, assessed a range of personality traits using widely-used personality inventories, and tested the relationship between the two. We found that there is, indeed, a relationship between personality and the typicality of brain activity, which appears to be most consistently manifested by lower typicality in subjects with higher Neuroticism/Harm Avoidance. Our results highlight the usefulness of naturalistic viewing data for exploring the relationship between individual differences in personality and brain activity.
SUN-domain proteins of the malaria parasitePlasmodium falciparumare essential for proper nuclear division and DNA repair
Authors: Kandelis-Shalev Sofiya , Goyal Manish , Elam Tal , Assaraf Shany , Dahan Noa , Farchi Omer , Berenshtein Eduard , Dzikowski Ron
Published: April 2024

The protozoan parasitePlasmodium falciparum, which is responsible for the deadliest form of human malaria, accounts for over half a million deaths a year. These parasites proliferate in human red blood cells by consecutive rounds of closed mitoses called schizogony. Their virulence is attributed to their ability to modify the infected red cells to adhere to the vascular endothelium and to evade immunity through antigenic switches. Spatial dynamics at the nuclear periphery were associated with regulation of processes that enable the parasites to establish long-term infection. However, our knowledge of components of the nuclear envelope (NE) inPlasmodiumremains limited. One of the major protein complexes at the NE is the LINC complex that forms a connecting bridge between the cytoplasm and the nucleus through the interaction of SUN and KASH domain proteins. Here we have identified two SUN-domain proteins as possible components of the LINC complex ofP. falciparumand show that their proper expression is essential for the parasite’s proliferation in human red blood cells and that their depletion leads to the formation of membranous whorls and morphological changes of the NE. In addition, their differential expression highlight different functions at the nuclear periphery as PfSUN2 is specifically associated with heterochromatin, while PfSUN1 expression is essential for activation of the DNA damage response. Our data provide indications for the involvement of the LINC complex in crucial biological processes in the intraerythrocytic development cycle of malaria parasites.
Inferring gene regulatory networks using DNA methylation data
Authors: Bartlett Thomas E. , Li Melodie , Huang Qiulin
Published: April 2024

We show much-improved accuracy of inference of GRN (gene regulatory network) structure, resulting from the use of an epigenomic prior network. We also find that DNAme data are very effective for inferring the epigenomic prior network, recapitulating known epigenomic network structure found previously from chromatin accessibility data, and typically providing potential TF cis-regulations for at least eight times as many genes when compared with chromatin accessibility data. When our proposed methodology is applied to real datasets from human embryonic development and from women at risk of breast cancer, we find patterns of differential cis-regulation that are in line with expectations under appropriate biological models, and that can be used to identify pre-cancerous epigenomic changes with valid functional genomic interpretations.
MARK2variants cause autism spectrum disorderviathe downregulation of WNT/β-catenin signaling pathway
Authors: Gong Maolei , Li Jiayi , Liu Yijun , Wilke Matheus Vernet Machado Bressan , Li Qian , Liu Haoran , Liang Chen , Morales-Rosado Joel A , Cohen Ana S.A. , Hughes Susan S. , Sullivan Bonnie R. , Waddell Valerie , van den Boogaard Marie-José H. , van Jaarsveld Richard H. , van Binsbergen Ellen , van Gassen Koen L , Wang Tianyun , Hiatt Susan M. , Amaral Michelle D. , Kelley Whitley V. , Zhao Jianbo , Feng Weixing , Ren Changhong , Yu Yazhen , Boczek Nicole J , Ferber Matthew J. , Lahner Carrie , Elliott Sherr , Ruan Yiyan , Cyril Mignot , Keren Boris , Xie Hua , Wang Xiaoyan , Popp Bernt , Zweier Christiane , Piard Juliette , Coubes Christine , Mau-Them Frederic Tran , Safraou Hana , Innes Micheil , Gauthier Julie , Michaud Jacques , Koboldt Daniel C. , Sylvie Odent , Willems Marjolaine , Tan Wen-Hann , Cogne Benjamin , Rieubland Claudine , Braun Dominique , McLean Scott Douglas , Platzer Konrad , Zacher Pia , Oppermann Henry , Evenepoel Lucie , Blanc Pierre , Khattabi Laïla El , Haque Neshatul , Dsouza Nikita R. , Zimmermann Michael T. , Urrutia Raul , Klee Eric W , Shen Yiping , Du Hongzhen , Qin Zailong , Liu Chang-Mei , Chen Xiaoli
Published: April 2024

MARK2, a member of the evolutionarily conserved PAR1/MARK serine/threonine kinase family, has been identified as a novel risk gene for autism spectrum disorder (ASD) based on the enrichment ofde novoloss-of-function (Lof) variants in large-scale sequencing studies of ASD individuals. However, the features shared by affected individuals and the molecular mechanism ofMARK2variants during early neural development remained unclear. Here, we report 31 individuals carrying heterozygousMARK2variants and presenting with ASD, other neurodevelopmental disorders, and typical facial dysmorphisms. Lof variants predominate (81%) in affected individuals, while computational analysis andin vitrotransfection assay also point toMARK2loss resulting from missense variants. Using patient-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), andMark2+/-(HET) mice, we show thatMARK2loss leads to systemic neurodevelopmental deficits, including anomalous polarity in neural rosettes, imbalanced proliferation and differentiation in neural progenitor cells (NPCs), abnormal cortical development and ASD-like behaviors in mice. Further using RNA-Seq and lithium treatment, we linkMARK2loss to the downregulated WNT/β-catenin signaling pathway and identify lithium as a potential drug for treatingMARK2-related ASD.
Prediction of Central Post-Stroke Pain by Quantitative Sensory Testing
Authors: Asseyer Susanna , Panagoulas Eleni , Maidhof Jana , Villringer Kersten , Al Esra , Chen Xiuhui , Krause Thomas , Hardikar Samyogita , Villringer Arno , Jungehülsing Gerhard Jan
Published: April 2024

Objective

Among patients with acute stroke, we aimed to identify those who will later develop central post-stroke pain (CPSP) versus those who will not (non-pain sensory stroke: NPSS) by assessing potential differences in somatosensory profile patterns and evaluating their potential as predictors of CPSP.

Methods

We performed a prospective longitudinal quantitative sensory testing (QST) study in 75 stroke patients with somatosensory symptoms, recruited in the acute phase and followed up for 12 months. Based on previous QST studies in chronic stroke, we hypothesised that QST values of cold detection threshold (CDT) and dynamic mechanical allodynia (DMA) would differ between CPSP and NPSS patients before the onset of pain. Mann-Whitney U-tests and mixed ANOVAs with Bonferroni corrections were performed to compare z-normalised QST scores between both groups.

Results

In total 26 patients (34.7%) developed CPSP. In the acute phase, CPSP patients showed significant contralesional cold hypoesthesia compared to NPSS patients (P= 0.04), but no significant DMA differences. Additional exploratory analysis showed NPSS patients exhibit cold hyperalgesia on the contralesional side compared to the ipsilesional side, not seen in CPSP patients (P= 0.011). A gradient-boosting approach to predicting CPSP from QST patterns prior to pain onset, had an overall accuracy of 84.6, with a recall and precision of 0.75. Notably, both in the acute and the chronic phase, about 80% of CPSP and NPSS patients showed bilateral QST abnormalities.

Interpretation

Cold perception differences between CPSP and NPSS patients appear early post stroke before pain. Prediction of CPSP through QST patterns seems feasible.
Associations of adolescent menstrual symptoms with school absences and educational attainment: analysis of a prospective cohort study
Authors: Sawyer Gemma , Fraser Abigail , Lawlor Deborah A. , Sharp Gemma C. , Howe Laura D.
Published: April 2024

Background

Menstrual symptoms may negatively impact pupils’ attendance and educational attainment, but rigorous population-based studies are lacking.

Methods

In a prospective cohort study in England, we assessed associations of self-reported heavy or prolonged bleeding and menstrual pain with school absences and attainment, adjusting for potential confounders.

Findings

Of 2,698 participants, 36% reported heavy or prolonged bleeding and 56% reported menstrual pain. Heavy or prolonged bleeding was associated with missing 1·7 additional days of school per year (16·58%; 95% CI: 9·43, 24·20), and 48% higher odds of being persistently absent (≥10% absent) (OR 1·48; 95% CI: 1·45, 1·52). Menstrual pain was associated with missing 1·2 additional days of school per year (12·83%; 95% CI: 6·14, 19·95), and 42% higher odds of being persistently absent (OR 1·42; 95% CI: 1·39, 1·46). Heavy or prolonged bleeding was associated with lower scores in compulsory examinations taken at age 16 (−5·7 points; 95% CI: −10·1, −1·2, equating to one lower grade), and with 27% lower odds of achieving five standard passes (OR 0·73; 95% CI: 0·71, 0·75). There was less evidence of an association between menstrual pain and examination scores (−3·14 points; 95% CI: - 7·46, 1·17), but menstrual pain was associated with 16% lower odds of achieving five standard passes (OR 0·84; 95 CI: 0·81, 0·86).

Interpretation

Both heavy or prolonged bleeding and menstrual pain were associated with lower school attendance and educational attainment. Greater research and support are needed to enable girls to achieve their full academic potential.

Funding

Wellcome Trust and UK Medical Research Council.
Enigmatic missense mutations can cause disease via creation ofde novonuclear export signals
Authors: McConville By Michael , Thomas Toby , Beckner Ryan , Valadez Catherine , Chook YuhMin , Chung Stephen , Liszczak Glen
Published: April 2024

Disease-causing missense mutations that occur within structurally and functionally unannotated protein regions can guide researchers to new mechanisms of protein regulation and dysfunction. Here, we report that the thrombocytopenia-, myelodysplastic syndromes-, and leukemia-associated P214L mutation in the transcriptional regulator ETV6 creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity. Mechanistic insight inspired the design of a ‘humanized’ ETV6 mice, which we employ to demonstrate that the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance. Beyond ETV6, we employed computational methods to uncover rare disease-associated missense mutations in unrelated proteins that create a nuclear export signal to disrupt protein function. Thus, missense mutations that operate through this mechanism should be predictable and may suggest rational therapeutic strategies for associated diseases.
Quinolone resistance genesqnr,aac(6′)-Ib-cr,oqxAB, andqepAin environmentalEscherichia coli: insights into their genetic contexts from comparative genomics
Authors: Gomi Ryota , Adachi Fumie
Published: April 2024

Previous studies have reported the occurrence of transferable quinolone resistance determinants in environmentalEscherichia coli. However, little is known about their vectors and genetic contexts. To gain insights into these genetic characteristics, we analyzed the complete genomes of 53 environmentalE. coliisolates containing one or more transferable quinolone resistance determinants, including 20 sequenced in this study and 33 sourced from RefSeq. The studied genomes carried the following transferable quinolone resistance determinants alone or in combination:aac(6′)-Ib-cr,oqxAB,qepA1,qnrA1,qnrB4,qnrB7,qnrB19,qnrD1,qnrS1, andqnrS2, withqnrS1being predominant. These resistance genes were detected on plasmids of diverse replicon types; however,aac(6′)-Ib-cr,qnrS1, andqnrS2were also detected on the chromosome. The genetic contexts surrounding these genes included not only those found in clinical isolates but also novel contexts, such asqnrD1embedded within a composite transposon-like structure bounded by Tn3-derived inverted-repeat miniature elements (TIMEs). This study provides deep insights into mobile genetic elements associated with transferable quinolone resistance determinants, highlighting the importance of genomic surveillance of antimicrobial resistant bacteria in the environment.
A library-based approach allows systematic and rapid evaluation of seed region length and reveals design rules for synthetic bacterial small RNAs
Authors: Brück Michel , Köbel Tania S. , Dittmar Sophie , Rojas Adán A. Ramírez , Georg Jens , Berghoff Bork A. , Schindler Daniel
Published: April 2024

All organisms must respond to environmental changes. In bacteria, small RNAs (sRNAs) are an important aspect of the regulation network underlying the adaptation to such changes. sRNAs base-pair with their target mRNAs, allowing rapid modulation of the proteome. This post-transcriptional regulation is usually facilitated by RNA chaperones, such as Hfq. sRNAs have a potential as synthetic regulators that can be modulated by rational design. In this study, we use a library-based approach and an oxacillin susceptibility assays to investigate the importance of the seed region length for synthetic sRNAs based on RybB and SgrS scaffolds inEscherichia coli. In the presence of Hfq we show that 12 nucleotides are sufficient for regulation. Furthermore, we observe a scaffold-specific Hfq-dependency and processing by RNase E. Our results provide information for design considerations of synthetic sRNAs in basic and applied research.
Identification of Suitable Target/E3 Ligase Pairs for PROTAC Development using a Rapamycin-induced Proximity Assay (RiPA)
Authors: Adhikari Bikash , Schneider Katharina , Diebold Mathias , Sotriffer Christoph , Wolf Elmar
Published: April 2024

The development of proteolysis targeting chimeras (PROTACs), which induce the degradation of target proteins by bringing them into proximity with cellular E3 ubiquitin ligases, has revolutionized drug development. While the human genome encodes more than 600 different E3 ligases, current PROTACs use only a handful of them, drastically limiting their full potential. Furthermore, many PROTAC development campaigns fail because the selected E3 ligase candidates are unable to induce degradation of the particular target of interest. As more and more ligands for novel E3 ligases are discovered, the chemical effort to identify the best E3 ligase for a given target is exploding. Therefore, a genetic system to identify degradation-causing E3 ligases and suitable target/E3 ligase pairs is urgently needed. Here we used the well-established dimerization of the FKBP12 protein and FRB domain by rapamycin to bring the target protein WDR5 into proximity with candidate E3 ligases. Strikingly, this rapamycin-induced proximity assay (RiPA) revealed that VHL, but not Cereblon, is able to induce WDR5 degradation - a finding previously made by PROTACs, demonstrating its predictive power. By optimizing the steric arrangement of all components and fusing the target protein with a minimal luciferase, RiPA can identify the ideal E3 for any target protein of interest in living cells, significantly reducing and focusing the chemical effort in the early stages of PROTAC development.
Exploring transient states of PAmKate to enable improved cryogenic single-molecule imaging
Authors: Perez Davis , Dowlatshahi Dara P. , Azaldegui Christopher A. , Ansell T. Bertie , Dahlberg Peter D. , Moerner W. E.
Published: April 2024

Super-resolved cryogenic correlative light and electron microscopy is a powerful approach which combines the single-molecule specificity and sensitivity of fluorescence imaging with the nano-scale resolution of cryogenic electron tomography. Key to this method is active control over the emissive state of fluorescent labels to ensure sufficient sparsity to localize individual emitters. Recent work has identified fluorescent proteins (FPs) which photoactivate or photoswitch efficiently at cryogenic temperatures, but long on-times due to reduced quantum yield of photobleaching remains a challenge for imaging structures with a high density of localizations. In this work, we explore the photophysical properties of the red photoactivatable FP PAmKate and identify a 2-color process leading to enhanced turn-off of active emitters, improving localization rate. Specifically, after excitation of ground state molecules, we find a transient state forms with a lifetime of ∼2 ms under cryogenic conditions which can be bleached by exposure to a second wavelength. We measure the response of the transient state to different wavelengths, demonstrate how this mechanism can be used to improve imaging, and provide a blueprint for study of other FPs at cryogenic temperatures.
Biochemical and structural insights into a 5’ to 3’ RNA ligase reveal a potential role in tRNA ligation
Authors: Hu Yingjie , Lopez Victor A. , Xu Hengyi , Pfister James P. , Song Bing , Servage Kelly A. , Sakurai Masahiro , Jones Benjamin T. , Mendell Joshua T. , Wang Tao , Wu Jun , Lambowitz Alan M. , Tomchick Diana R. , Pawłowski Krzysztof , Tagliabracci Vincent S.
Published: April 2024

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5’-phosphate and a 3’-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loopin vitro. Genetic depletion ofc12orf29in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog fromYasminevirusbound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

Significance Statement

ATP-grasp enzymes share an atypical ATP-binding fold and catalyze a diverse set of reactions involved in many essential cellular processes. We identified C12orf29 as an atypical ATP-grasp enzyme. Our biochemical and structural characterizations reveal this enzyme to be a 5’ to 3’ RNA ligase, structurally and functionally similar to the phage T4 RNA ligase. C12orf29 can ligate tRNAsin vitroand C12orf29 knockout female mice have altered tRNA levels in brain. We also report structures of C12orf29, which have revealed critical insights into the mode of ATP binding and catalysis. Our work suggests that C12orf29 may be a new player in the regulation of tRNAs.
Intelligent soaring and path planning for solar-powered unmanned aerial vehicles
Authors: Wu Yansen , Wen Dongsheng , Zhao Anmin , Liu Haobo , Li Ke
Published: April 2024

Purpose

This study aims to study the thermal identification issue by harvesting both solar energy and atmospheric thermal updraft for a solar-powered unmanned aerial vehicle (SUAV) and its electric energy performance under continuous soaring conditions.

Design/methodology/approach

The authors develop a specific dynamic model for SUAVs in both soaring and cruise modes. The support vector machine regression (SVMR) is adopted to estimate the thermal position, and it is combined with feedback control to implement the SUAV soaring in the updraft. Then, the optimal path model is built based on the graph theory considering the existence of several thermals distributed in the environment. The procedure is proposed to estimate the electricity cost of SUAV during flight as well as soaring, and making use of dynamic programming to maximize electric energy.

Findings

The simulation results present the integrated control method could allow SUAV to soar with the updraft. In addition, the proposed approach allows the SUAV to fly to the destination using distributed thermals while reducing the electric energy use.

Originality/value

Two simplified dynamic models are constructed for simulation considering there are different flight mode. Besides, the data-driven-based SVMR method is proposed to support SUAV soaring. Furthermore, instead of using length, the energy cost coefficient in optimization problem is set as electric power, which is more suitable for SUAV because its advantage is to transfer the three-dimensional path planning problem into the two-dimensional.