bluuebunny/crossref_metadata_2025 huggingface dataset:
Yanghe Pingchuan granules mitigates oxidative stress and inflammation in a bronchial asthma rat model: role of the IKK/IκB/NF-κB signalling pathway
Authors: Pan Lingyu , Gong Chunxia , Chen Yan , Jiang Yeke , Sun Yehong , He Bangfu , Duan Xianchun , Han Yanquan , Wang Yongzhong
Published: November 2023

Background:

Bronchial asthma (BA) is a chronic inflammatory airway disease. Previous research has shown that Yanghe Pingchuan granules (YPG), among the granules formulated by the First Affiliated Hospital of the Anhui University of Chinese Medicine, exerts a precise therapeutic effect on BA. We previously showed that YPG improves airway inflammation in BA rats. Other studies have shown that the inhibitor of kappa-B kinase (IKK)/inhibitor of NF-κB (IκB)/nuclear factor kappa-B (NF-κB) signalling pathway plays a key role in inflammation mediation. Therefore, this study explored whether YPG could intervene in BA through the IKK/IκB/NF-κB signalling pathway.

Methods:

Ovalbumin-induced method was used to established BA rat model. After successful modelling, the authors used YPG to intervene the rats in BA rats. Hematoxylin-eosin (HE) staining was used to detect the bronchial pathological changes in BA rats, enzyme-linked immunosorbent assay (ELISA) was used to detect the changes of inflammatory factors (IL-1β and IL-6) and oxidative stress indexes malondialdehyde (MDA), superoxide dismutase (SOD) and nitrogen monoxide (NO), Quantitative real-time polymerase chain reactionCR and western blot were used to detect the expression of IKK/IκB/NF-κB signalling pathway.

Results:

In BA model rats, YPG significantly improved the inflammatory response in bronchial tissues, reduced inflammatory factors IL-1β and IL-6, alleviated oxidative stress, reduced MDA and NO, and increased SOD. Quantitative real-time polymerase chain reaction and western blot results showed that YPG could block the IKK/IκB/NF-κB signalling pathway.

Conclusion:

These findings showed that YPG had a definite therapeutic effect on BA, which may be related to blocking the IKK/IκB/NF-κB signalling pathway and improving inflammation and oxidative stress.
An Adolescent Female With Concurrent Presentation of Autoimmune Hepatitis and Secondary Syphilis
Authors: Riddell Madison , Novak Chris , Dinn Sarah , Galante Gary
Published: November 2023

We describe concurrent diagnoses of autoimmune hepatitis (AIH) and secondary syphilis in a 17-year-old adolescent with jaundice, with possible syphilitic hepatitis (SH) excluded after a thorough investigation. Our patient presented with a several-day history of malaise, progressive jaundice, and vomiting. She disclosed being sexually active and requested testing for sexually transmitted infections. Her subsequent investigations demonstrated acute hepatitis with a positive antinuclear antibody and elevated IgG. She also tested positive for syphilis with a reactive rapid plasma regain and treponema pallidum particle agglutination assay. We considered 2 etiologies for her elevated liver enzymes: syphilitic hepatitis and AIH. AIH was confirmed on liver biopsy, establishing the first reported pediatric case of concurrent AIH and secondary syphilis. Syphilis is hypothesized to be an infectious trigger for AIH.
Jumping Trends In Trampoline-Related Craniofacial Injuries
Authors: Gompels Matthew T. , Treger Dylan , Mangal Rohan , Prasad Soumil , Thaller Seth R.
Published: November 2023

Introduction:

In 1990, the American Academy of Pediatrics recommended the sale of trampolines cease in the United States. The risk of traumatic injury is well-documented, yet trampolines remain a growing source of recreation. Trampoline parks, in particular, are becoming a common entertainment attraction that can result in serious injury. There is currently a paucity of literature characterizing craniofacial injuries from trampoline use and plans to prevent these injuries.

Methods and Materials:

A retrospective review of the National Electronic Injury Surveillance System was conducted to analyze emergency department visits for trampoline-related craniofacial injuries in 1 to 20 year olds between 2013 and 2022.

Results:

An estimated 206,866 trampoline-related craniofacial injuries occurred. Males suffered injuries 1.67 times more frequently than females. Injured sites included the head (41.0%), face (23.2%), neck (20.4%), mouth (11.9%), eyeball (2.0%), and ear (1.4%). The most common diagnoses were lacerations (28.9%), internal injuries (23.2%), strain/sprains (14.8%), contusions/abrasions (13.0%), and concussions (8.7%). Head internal injuries and facial lacerations significantly increased over the observed time period.

Discussion:

Trampolines are a rising source of craniofacial trauma for America’s youth. Children between 3 and 11 years old were disproportionately affected. Regulation over trampoline safety features remains limited in the United States. Future studies should aim to characterize the mechanisms of these injuries for the development of targeted safety measures.
ALTERED PROFILES OF EXTRACELLULAR MITOCHONDRIAL DNA IN IMMUNOPARALYZED PEDIATRIC PATIENTS AFTER THERMAL INJURY
Authors: Tetri Laura H. , Penatzer Julia A , Tsegay Kaleb B , Tawfik Daniel S. , Burk Shelby , Lopez Ivan , Thakkar Rajan K. , Haileselassie Bereketeab
Published: November 2023

Background:Thermal injury is a major cause of morbidity and mortality in the pediatric population worldwide with secondary infection being the most common acute complication. Suppression of innate and adaptive immune function is predictive of infection in pediatric burn patients, but little is known about the mechanisms causing these effects. Circulating mitochondrial DNA (mtDNA), which induces a proinflammatory signal, has been described in multiple disease states but has not been studied in pediatric burn injuries. This study examined the quantity of circulating mtDNA and mtDNA mutations in immunocompetent (IC) and immunoparalyzed (IP) pediatric burn patients.Methods:Circulating DNA was isolated from plasma of pediatric burn patients treated at Nationwide Children’s Hospital Burn Center at early (1–3 days) and late (4–7 days) time points postinjury. These patients were categorized as IP or IC based on previously established immune function testing and secondary infection. Three mitochondrial genes, D loop, ND1, and ND4, were quantified by multiplexed qPCR to assess both mtDNA quantity and mutation load.Results:At the early time point, there were no differences in plasma mtDNA quantity; however, IC patients had a progressive increase in mtDNA over time when compared with IP patients (change in ND1 copy number over time 3,880 vs. 87 copies/day,P= 0.0004). Conversely, the IP group had an increase in mtDNA mutation burden over time.Conclusion:IC patients experienced a significant increase in circulating mtDNA quantity over time, demonstrating an association between increased mtDNA release and proinflammatory phenotype in the burn patients. IP patients had significant increases in mtDNA mutation load likely representative of degree of oxidative damage. Together, these data provide further insight into the inflammatory and immunological mechanisms after pediatric thermal injury.
Anti-CD49d Antibody Treatment Improves Survival and Attenuates Neurocognitive Deficits after Traumatic Brain Injury in Aged Mice
Authors: Chen Zhangying , Ford Kacie , Islam Mecca , Iamsawat Supinya , Davis Booker , Weiss Craig , Schwulst Steven
Published: November 2023

Patients aged 65 and older account for an increasing proportion of traumatic brain injury (TBI) patients. Aged TBI patients suffer increased morbidity and mortality compared to young TBI patients. We previously demonstrated a marked accumulation of CD8 + T-cells within the brains of aged TBI mice compared to young TBI mice. Therefore, we hypothesized that blocking peripheral T-cell infiltration into the injured brain would improve neurocognitive outcomes in aged mice after TBI. Young and aged male C57BL/6 mice underwent TBI via controlled cortical impact vs. sham injury. Two hours-post injuries, mice received an anti-CD49d antibody (aCD49d Ab) to block peripheral lymphocyte infiltration or its isotype control. Dosing was repeated every two weeks. Mortality was tracked. Neurocognitive testing for anxiety, associative learning, and memory was assessed. Motor function was evaluated. Plasma was collected for cytokine analysis. Flow cytometry was employed to phenotype different immune cells within the brains. Consequently, aCD49d Ab treatment significantly improved post-TBI survival, anxiety level, associative learning, memory, and motor function in aged mice two months post-TBI compared to isotype control treated mice. aCD49d Ab treatment augmented Th2 response in the plasma of aged mice two months post-TBI compared to isotype control-treated mice. Notably, aCD49d Ab treatment significantly reduced activated CD8+ cytotoxic T-cells within aged mouse brains after TBI. Contrastingly, no difference was detected in young mice after aCD49d Ab treatment. Collectively, aCD49 Ab treatment reduced T-cells in the injured brain, improved survival, and attenuated neurocognitive and gait deficits. Hence, aCD49d Ab may be a promising therapeutic intervention in aged TBI subjects—a population often excluded in TBI clinical trials.
CIRC_0003907 MODULATES SEPSIS-INDUCED MYOCARDIAL INJURY VIA ENHANCING MYD88/NLRP3/NF-ΚB AXIS BY SPONGING MIR-944
Authors: Lv Wei , Liu Hui , Wang Xin , Hao Rui
Published: November 2023

Background: Sepsis-induced cardiomyopathy (SIC) is a common complication of sepsis with high morbidity and mortality but lacks specific therapy. The purpose of this study was to investigate the role of circularRNA_0003907 (circ_0003907) in myocardium injury induced by sepsis. Methods: In this experiment, human AC16 cells were treated with lipopolysaccharide (LPS) to induce an in vitro cardiomyocyte injury model. Expression of circ_0003907, microRNA-944 (miR-944), and MYD88 was detected using quantitative real-time polymerase chain reaction. Cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, thymidine analog 5-ethynyl-2′-deoxyuridine, and flow cytometry assays. Secretions of proinflammatory cytokines IL-6 and TNF-α were detected using ELISA kits. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were detected using special kits. Protein levels of cyclin D1, cleaved caspase-3, MYD88, NLRP3, P65, and IκBα were determined using western blot assay. After being predicted using Circineractome and starBase, the interaction between miR-944 and circ_0003907 or MYD88 was confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0003907 expression was increased in serum from SIC patients and in LPS-treated AC16 cells. Circ_0003907 knockdown might abolish LPS-triggered proliferation inhibition, and the promotion of apoptosis, inflammatory response, and oxidative stress in AC16 cells. In mechanism, circ_0003907 acted as a sponge for miR-944 to increase MYD88 expression. Meanwhile, the absence of circ_0003907 induced miR-944 expression and suppressed MYD88/NLRP3/NF-κB levels. Conclusion: Circ_0003907 sponged miR-944 to aggravate LPS-induced AC16 cell dysfunction via activating the MYD88/NLRP3/NF-κB axis during sepsis, which might provide a new direction for the treatment of SIC.
DIFFERENCES IN MANAGEMENT AND PROGNOSTICATION OF CARDIOGENIC SHOCK PATIENTS IN THE PRESENCE AND ABSENCE OF OUT-OF-HOSPITAL CARDIAC ARREST
Authors: Mieritz Hanne Beck , Povlsen Amalie Ling , Linde Louise , Beske Rasmus Paulin , Helgestad Ole Kristian Lerche , Josiassen Jakob , Hassager Christian , Schmidt Henrik , Jensen Lisette Okkels , Holmvang Lene , Møller Jacob Eifer , Ravn Hanne Berg
Published: November 2023

Background: The clinical spectrum of acute myocardial infarction complicated by cardiogenic shock (AMICS) varies. Out-of-hospital cardiac arrest (OHCA) can be the first sign of cardiac failure, whereas others present with various degrees of hemodynamic instability (non-OHCA). The aim of the present study was to explore differences in prehospital management and characteristics of survivors and nonsurvivors in AMICS patients with OHCA or non-OHCA. Methods: Data analysis was based on patient data from the RETROSHOCK cohort comprising consecutive AMICS patients admitted to two tertiary cardiac centers between 2010 and 2017. Results: 1,716 AMICS patients were included and 42% presented with OHCA. Mortality in OHCA patients was 47% versus 57% in the non-OHCA group. Almost all OHCA patients were intubated before admission (96%). In the non-OHCA group, prehospital intubation (25%) was associated with a better survival (P < 0.001). Lactate level on admission demonstrated a linear relationship with mortality in OHCA patients. In non-OHCA, probability of death was higher for any given lactate level <12 mmol/L compared with OHCA. However, a lactate level >7 mmol/L in non-OHCA did not increase mortality odds any further. Conclusion: Mortality was almost doubled for any admission lactate level up to 7 mmol/L in non-OHCA patients. Above this level, mortality remained unchanged in non-OHCA patients but continued to increase in OHCA patients. Prehospital intubation was performed in almost all OHCA patients but only in one of four patients without OHCA. Early intubation in non-OHCA patients was associated with a better outcome.
Impact of high-dose vasopressor during endotoxic shock on the cerebral, lingual, hepatic, and renal microcirculation evaluated by near-infrared spectroscopy in swine
Authors: Kurita Tadayoshi , Kawashima Shingo , Khaleelullah Mohamed Mathar Sahib Ibrahim , Nakajima Yoshiki
Published: November 2023

Background

High-dose vasopressors maintain blood pressure during septic shock but may adversely reduce microcirculation in vital organs. We assessed the effect of high-dose norepinephrine and vasopressin on the microcirculation of the brain, tongue, liver, and kidney during endotoxic shock using near-infrared spectroscopy (NIRS).

Methods

Thirteen pigs (24.5 ± 1.8 kg) were anesthetized, and an NIRS probe was attached directly to each organ. Approximately 0.2, 0.5, 1, and 2 μg/kg/min of norepinephrine were administered in a stepwise manner, followed by 0.5, 1, 2, and 5 μg/kg/min of sodium nitroprusside in normal condition. Moreover, 1 μg/kg/h of lipopolysaccharide was administered continuously after 100 μg bolus to create endotoxic shock, and after 1000 mL of crystalloid infusion, high-dose norepinephrine (2, 5, 10, and 20 μg/kg/min) and vasopressin (0.6, 1.5, 3, and 6 U/min) were administered in a stepwise manner. The relationship between the mean arterial pressure (MAP) and each tissue oxygenation index (TOI) during vasopressor infusion was evaluated.

Results

Three pigs died after receiving lipopolysaccharides, and 10 were analyzed. An increase of >20% from the baseline MAP induced by high-dose norepinephrine during endotoxic shock reduced the TOI in all organs except the liver. The elevation of MAP to baseline with vasopressin alone increased the kidney and liver TOIs and decreased the tongue TOI.

Conclusions

Forced blood pressure elevation with high-dose norepinephrine during endotoxic shock decreased the microcirculation of vital organs, especially the kidney. Cerebral TOI may be useful for identifying the upper limit of blood pressure, at which norepinephrine impairs microcirculation.
Pilot study of frozen platelet extracellular vesicles as a therapeutic agent in hemorrhagic shock in rats
Authors: Durbin Samantha , Loss Lindsey , Buzzard Lydia , Minoza Karen , Beiling Marissa , Karsonovich Carmen , Liu Moqing , Garay Joseph , Fields Alexander , Mathews Michael , Kuhn Benjamin , Moskowitz Keith , Miyazawa Byron , Trivedi Alpa , Kornblith Lucy , Fitzpatrick Michael , Pati Shibani , Schreiber Martin
Published: November 2023

BACKGROUND

Hemorrhage accounts for the most preventable deaths after trauma. Resuscitation is guided by studies that demonstrate improved outcomes in patients receiving whole blood or balanced administration of blood products. Platelets present a logistical challenge due to short shelf life and need for refrigeration. Platelet-derived extracellular vesicles (PEVs) are a possible platelet alternative. Platelet-derived extracellular vesicles are secreted from platelets, have hemostatic effects and mitigate inflammation and vascular injury, similar to platelets. This pilot study aimed to elucidate the therapeutic effects of PEVs in a rat model of uncontrolled hemorrhage.

METHODS

Male rats were anesthetized and femoral vessels cannulated. Vital signs (MAP, HR, and RR) were monitored. Electrolytes, lactate and ABG were obtained at baseline, 1-hour and 3-hours post injury. Laparotomy was performed, 50% of the middle hepatic lobe excised and the abdomen packed with gauze. Rats received 2 mL PEVs or lactated Ringers (LR) over 6 minutes immediately after injury. Peritoneal blood loss was quantified using preweighed gauze at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes. Laparotomy was closed 1-hour postinjury. Animals were monitored for 3 hours postinjury then euthanized. Generalized Linear Mixed Effects models were performed to assess effects of treatment and time on lactate and MAP.

RESULTS

Twenty-one rats were included (11 LR, 10 PEV). Overall blood loss was between 6 mL and 10 mL and not significantly different between groups. There was a 36% mortality rate in the LR group and 0% mortality in the PEV group (p = 0.03). The LR group had significantly higher lactates at 1 hour (p = 0.025). At 15 minutes, 45 minutes, 60 minutes, and 180 minutes, the MAP of the PEV group was significantly higher than the LR group.

CONCLUSION

Early studies are encouraging regarding the potential use of PEVs in uncontrolled hemorrhagic shock based on improved survival and hemodynamics.
Deepfake detection with and without content warnings
Authors: Lewis Andrew , Vu Patrick , Duch Raymond M. , Chowdhury Areeq
Published: November 2023

The rapid advancement of ‘deepfake' video technology—which uses deep learning artificial intelligence algorithms to create fake videos that look real—has given urgency to the question of how policymakers and technology companies should moderate inauthentic content. We conduct an experiment to measure people's alertness to and ability to detect a high-quality deepfake among a set of videos. First, we find that in a natural setting with no content warnings, individuals who are exposed to a deepfake video of neutral content are no more likely to detect anything out of the ordinary (32.9%) compared to a control group who viewed only authentic videos (34.1%). Second, we find that when individuals are given a warning that at least one video in a set of five is a deepfake, only 21.6% of respondents correctly identify the deepfake as the only inauthentic video, while the remainder erroneously select at least one genuine video as a deepfake.
Strongyloides
questions—a research agenda for the future
Authors: Al-Jawabreh Reem , Anderson Roy , Atkinson Louise E. , Bickford-Smith Jack , Bradbury Richard S. , Breloer Minka , Bryant Astra S. , Buonfrate Dora , Cadd Luke C. , Crooks Bethany , Deiana Michela , Grant Warwick , Hallem Elissa , Hedtke Shannon M. , Hunt Vicky , Khieu Virak , Kikuchi Taisei , Kounosu Asuka , Lastik Dominika , van Lieshout Lisette , Liu Yuchen , McSorley Henry J. , McVeigh Paul , Mousley Angela , Murcott Ben , Nevin William David , Nosková Eva , Pomari Elena , Reynolds Kieran , Ross Kirstin , Streit Adrian , Suleiman Mona , Tiberti Natalia , Viney Mark
Published: November 2023

The
Strongyloides
genus of parasitic nematodes have a fascinating life cycle and biology, but are also important pathogens of people and a World Health Organization-defined neglected tropical disease. Here, a community of
Strongyloides
researchers have posed thirteen major questions about
Strongyloides
biology and infection that sets a
Strongyloides
research agenda for the future.

This article is part of the Theo Murphy meeting issue ‘
Strongyloides
: omics to worm-free populations’.
Development of a novel streamlined workflow (AACRE) and database (inCREDBle) for genomic analysis of carbapenem-resistant Enterobacterales
Authors: Alioto Tyler S. , Gut Marta , Rodiño-Janeiro Bruno Kotska , Cruz Fernando , Gómez-Garrido Jèssica , Vázquez-Ucha Juan Carlos , Mata Caterina , Antoni Regina , Briansó Ferran , Dabad Marc , Casals Eloi , Ingham Matthew , Álvarez-Tejado Miguel , Bou Germán , Gut Ivo G.
Published: November 2023

In response to the threat of increasing antimicrobial resistance, we must increase the amount of available high-quality genomic data gathered on antibiotic-resistant bacteria. To this end, we developed an integrated pipeline for high-throughput long-read sequencing, assembly, annotation and analysis of bacterial isolates and used it to generate a large genomic data set of carbapenemase-producing Enterobacterales (CPE) isolates collected in Spain. The set of 461 isolates were sequenced with a combination of both Illumina and Oxford Nanopore Technologies (ONT) DNA sequencing technologies in order to provide genomic context for chromosomal loci and, most importantly, structural resolution of plasmids, important determinants for transmission of antimicrobial resistance. We developed an informatics pipeline called Assembly and Annotation of Carbapenem-Resistant Enterobacteriaceae (AACRE) for the full assembly and annotation of the bacterial genomes and their complement of plasmids. To explore the resulting genomic data set, we developed a new database called inCREDBle that not only stores the genomic data, but provides unique ways to filter and compare data, enabling comparative genomic analyses at the level of chromosomes, plasmids and individual genes. We identified a new sequence type, ST5000, and discovered a genomic locus unique to ST15 that may be linked to its increased spread in the population. In addition to our major objective of generating a large regional data set, we took the opportunity to compare the effects of sample quality and sequencing methods, including R9 versus R10 nanopore chemistry, on genome assembly and annotation quality. We conclude that converting short-read and hybrid microbial sequencing and assembly workflows to the latest nanopore chemistry will further reduce processing time and cost, truly enabling the routine monitoring of resistance transmission patterns at the resolution of complete chromosomes and plasmids.
Effects of Buprenorphine, Methadone and Substance-Use on COVID-19 Morbidity and Mortality
Authors: Christian Nicholaus , Zhou Xin , Radhakrishnan Rajiv
Published: November 2023

Objectives

Substance use disorder has been associated with increased morbidity in COVID-19 infection. However, less is known about the impact of active substance use and medications for opioid use disorder (MOUD) on COVID-19 outcomes. We conducted a retrospective cohort study to evaluate the impact of substance use, namely cannabis, cocaine, alcohol, sedative and opioid use as well as buprenorphine or methadone = on COVID-19 morbidity and mortality.

Methods

Using electronic-health record data at a large urban hospital system, patients who tested positive for COVID-19 between January 1, 2020 to December 31, 2021 were included. Substance use was identified from urine toxicology and MOUD prescriptions within 90 days prior to admission. COVID-19 outcomes included mortality, ICU admission, need for ventilatory support, number and duration of hospitalizations. Multivariable logistic regression was performed controlling for variables such as age, sex, medical comorbidity, tobacco use, and social disadvantage.

Results

Among COVID-19 positive patients (n=17,423), sedative, cannabis, cocaine, and opioid use was associated with statistically significant increases in need for ICU care, need for ventilatory support, number of hospitalizations and duration of hospitalization. Substance use was not associated with an increase in all-cause mortality. There were no statistically significant differences between methadone, buprenorphine and other opioids on COVID-19 outcomes.

Conclusions

Active substance use were associated with increased morbidity in COVID-19 infection. MOUD was not associated with worse COVID-19 outcomes compared to OUD. Future studies focused on MOUD treatments that reduce morbidity may help improve clinical outcomes in COVID-19.
Genomic selection for herbage yield in forage oats (Avena sp.)
Authors: Rocha Dediel A. , Cordova Ulisses A. , Flaresso Jefferson , Stradiotto Joseli
Published: November 2023

The study investigated the potential of genomic selection (GS) to accelerate genetic improvement in forage oats (Avena sp.) by predicting herbage yield. The results showed that GS can be an effective tool for predicting herbage yield in forage oats, with prediction accuracies ranging from 0.91 to 0.97. The use of SNP markers for GS in forage oats has several advantages over traditional marker-assisted selection (MAS), including the ability to capture more of the genetic variation for the trait of interest. The accuracy of GS predictions can be further improved by using trait-specific relationship matrices (TGRMs) and genomic information from multiple generations.

Key Findings

GS can be an effective tool for predicting herbage yield in forage oats, with prediction accuracies ranging from 0.91 to 0.97.

The use of SNP markers for GS in forage oats has several advantages over traditional MAS, including the ability to capture more of the genetic variation for the trait of interest.

The accuracy of GS predictions can be further improved by using TGRMs and genomic information from multiple generations.

Implications

GS can be used to accelerate the development of new forage oat varieties with improved herbage yield.

GS has the potential to significantly improve the agronomic performance and quality of forage oat varieties.

Future Research

Develop a more structured training population to improve the accuracy of GS predictions.

Identify trait-specific relationship matrices (TGRMs) to further improve the accuracy of GS predictions.

Investigate the use of genomic information from multiple generations to improve the accuracy of GS predictions.
Origin of evolutionary bifurcation in an enzyme
Authors: Miton Charlotte M. , Campbell Eleanor C. , Kaczmarski Joe A. , Feixas Ferran , Romero-Rivera Adrian , Sandhu Mahakaran , Anderson Dave W. , Shatani Naoya , Osuna Sílvia , Jackson Colin J. , Tokuriki Nobuhiko
Published: November 2023

Evolution can lead to significantly distinct outcomes depending on the mutational path taken. Evolutionary bifurcation, in which two mutational trajectories segregate, becoming non-interchangeable over time, is the basis of diversification in all kingdoms of life. Here, we present a detailed molecular description of a bifurcation event that rapidly led to the emergence of two distinct enzymes from a common ancestor. When initiated from two starting points that differed by a single amino acid, the laboratory evolution of a phosphotriesterase (PTE) toward arylester hydrolysis resulted in different genetic and phenotypic outcomes. One trajectory led to a >35,000-fold increase in activityviathe reorganization of its active site to achieve exquisite enzyme-substrate complementarity. The second trajectory gave rise to an evolved variant with a ∼500-fold increase in activity, but exhibiting an alternative substrate binding mode resulting from the destabilization of an active site loop. While initial mutations tend to dictate mutational accessibility, we rather observed the gradual divergence and specialisation of each trajectory, following the emergence of distinct molecular interaction networks. Intramolecular epistasis underlay pathway bifurcation by promoting unique synergistic interactions within each trajectory, while restricting the fixation of mutation across pathways. Our results illustrate how distinct molecular outcomes can radiate from a common protein ancestor and give rise to phenotypic diversity.
Machine learning analysis of lung adenocarcinoma and squamous cell carcinoma microbiome datasets reveals biomarkers for early diagnosis
Authors: Kashyap Pragya , Raj Kalbhavi Vadhi , Dutt Naveen , Yadav Pankaj
Published: November 2023

Introduction

Lung cancer (LC) is the second most frequent cancer worldwide with high incidences and mortality rates and non-small-cell-lung cancer (NSCLC) accounts for 80-85% cases of LC. It is further majorly sub-classified into adenocarcinoma (AC), and squamous-cell carcinoma (SCC). A late diagnosis at an advanced stage, a high rate of metastasis, and the development of therapy resistance are responsible for approximately 95% of mortality. Owing to high heterogeneity and variances in subtypes, it is important to precisely classify them for treatment. However, it poses a challenge in clinical practices, as it requires accurate quantification of each proportion subtype which is time-consuming and sometimes erroneous. The lower airways are home to a dynamic bacterial population sustained by the immigration, elimination, and migration of microbes from the gastrointestinal tract and upper airway tracts. The disruption in the homeostasis of microbiome compositions was found to be correlated with the increased risk of LC. Artificial intelligence (AI) techniques are used extensively in the early screening, and treatment of NSCLC have made significant strides in recent years. Recently, the use of CT/MRI scan image data in prediction models also results in false-positive rates and requires subsequent tests for further exploration which delays the prognostication. Therefore, early diagnosis, prevention, and treatment are critical to enhance survival and reduce death. Here, we aim for the classification of AC and SCC using the lung microbiome of lung tissue samples, implementing AI-based algorithms.

Methods

We have obtained raw sequencing data from the NCBI online database, and 149 AC samples and 145 SCC samples in patients were analyzed for their lung microbiome present in the lung tissue samples. The metadata such as patient age, sex, smoking history, and environmental material (malignant or not) were also analyzed. Using these data, machine learning algorithms were applied to select the best microbiome features for the classification of subtypes.

Results

A supervised ML and DL based model was developed that can discriminate NSCLC subtypes based on their microbial information, exploring the microbiome as predictive information for early screening. Consequently, 17 features were identified as a biomarker, and they showed good performance in distinguishing AC from SCC with an accuracy of 81% in KNN and 71% in DNN when demonstrated on the validation dataset.

Conclusion

This study proposed a supervised machine learning framework where we can rely on taxonomic features and AI techniques to classify overlapped AC and SCC metagenomic data providing lung microbiome as a predictive and diagnostic biomarker in LC. Moreover, our framework will also be very helpful to other researchers to obtain further biomarkers and perform analysis in overlapped subtypes in different diseases.
Tracking the misallocation and reallocation of spatial attention towards auditory stimuli
Authors: Mandal Ananya , Liesefeld Anna M. , Liesefeld Heinrich R.
Published: November 2023

Completely ignoring a salient distractor presented concurrently with a target is difficult and sometimes attention is involuntarily attracted to the distractor’s location (attentional capture). Employing the N2ac component as a marker of attention allocation towards sounds, in this study we investigate the spatio-temporal dynamics of auditory attention across two experiments. Human participants (male and female) performed an auditory search task, where the target was accompanied by a distractor in 2/3rd of the trials. For a distractor more salient than target (Exp. 1), we observe not only a distractor N2ac (indicating attentional capture), but the full chain of attentional dynamics implied by the notion of attentional capture, namely: (a) the distractor captures attention before the target is attended, (b) allocation of attention to the target is delayed by distractor presence, and (c) the target is attended after the distractor. Conversely, for a distractor less salient than the target (Exp. 2), although behavioral interference was present, no attentional capture was observed. Together, these findings reveal two types of spatial-attentional dynamics in the auditory modality (distraction with and without attentional capture).

Significance Statement

Oftentimes, we find it hard to ignore the location of a salient sound that distracts us from our current tasks. Although, a common everyday experience, little is known about how spatial distraction unfolds at the neural level in the auditory modality. Using electrophysiological markers of attention allocations, we report comprehensive evidence of spatial attentional capture by a salient auditory distractor, indicating that attention is first misallocated to the distractor and only afterwards reallocated towards the target. Similar patterns were observed earlier only in vision and their discovery in the auditory modality indicates towards the existence of domain-general spatial attentional dynamics consistent across sensory modalities. Finally, we demonstrate that only a distractor more salient than the target reliably captures attention.
Increased offspring size and reduced gestation length in an ectothermic vertebrate under a worst-case climate change scenario
Authors: Hubert David L , Bentz Ehren J , Mason Robert T
Published: November 2023

As global temperatures continue to increase, understanding the impacts of warming environments is increasingly relevant. Temperature is especially relevant for ectothermic organisms which depend upon consistent and predictable annual temperature cycles for reproduction and development. However, additional research is required in this area to elucidate the potential impacts of climate change on future generations. To understand how projected increases in environmental temperatures may impact reproductive outcomes within natural populations of ectothermic vertebrates, we manipulated minimum ambient temperatures during gestation in Red-sided garter snakes (Thamnophis sirtalis parietalis). Wild snakes were collected in the Interlake region of Manitoba, Canada during their spring mating season and allowed to mate in controlled conditions. For the duration of gestation, mated females were placed into one of two ambient thermal conditions: temperatures emulating those found in the species’ natural habitat or temperatures with a consistent 5 °C increase to match end-of-century climate change projections. We recorded observations for each litter and all neonates resulting from controlled mating trials. We observed no difference in litter sizes or birth rates between thermal conditions. However, we observed a significant reduction in gestation length and significant increase to neonate body mass and body condition associated with increased ambient temperatures. These results suggest that increased minimum temperatures during gestation may confer reproductive benefits for the northern populations of this species even under the most extreme current modeled warming predictions. We discuss the broader implications of this effect, including possible negative ecological outcomes.
Exploring connectivity of resting-state EEG between BCI-literate and -illiterate groups
Authors: Park Hanjin , Jun Sung Chan
Published: November 2023

Although Motor Imagery-based Brain-Computer Interface (MI-BCI) holds significant potential, its practical application faces challenges attributable to the phenomenon known as BCI-illiteracy. BCI researchers have attempted to predict BCI-illiteracy to mitigate this issue. As connectivity’s significance in neuroscience has grown, BCI researchers have applied connectivity to predict BCI-illiteracy with resting-state data. However, connectivity metrics’ use and interpretation of the results can be challenging for several reasons. Firstly, there are various connectivity metrics, each with its own advantages and disadvantages based on their underlying hypotheses and perspectives. These pros and cons are shaped by several factors, increasing the complexity of their application and interpretation. Secondly, it is unclear whether they are as acceptable as their developers have claimed. Thirdly, it is not evident which factor may influence the estimation of connectivity and which metric is suitable for this research. Therefore, this study conducted an empirical test to provide BCI researchers with a better understanding of connectivity. We analyzed three large public datasets using three functional connectivity (FC) and three effective connectivity (EC) metrics. Additionally, the structural difference in the resting-state network between BCI-literate and illiterate groups was examined. Our analysis revealed that the appropriate frequency range to measure connectivity varies depending upon the metric used. The alpha range was found to be suitable for FC, while the alpha, alpha + theta, and beta ranges were found to be appropriate for EC. Further, the results of estimating connectivity varied depending upon the dataset and metric used. Although we observed that BCI-literacy had stronger connections between nodes, no other significant structural differences were found between the two groups. However, BCI-literacy’s resting-state network displayed higher network efficiency compared to BCI-illiteracy, regardless of the metrics and dataset used. Therefore, it seems reasonable to use resting-state connectivity to predict BCI-illiteracy. Our conclusion is that each metric has its own specific hypothesis and perspective to measure connectivity under certain conditions.
H2A.Z chaperones converge on histone H4 acetylation for melanoma cell proliferation
Authors: Jostes Sina , Vardabasso Chiara , Dong Joanna , Carcamo Saul , Singh Rajendra , Phelps Robert , Meadows Austin , Hasson Dan , Bernstein Emily
Published: November 2023

High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes, SRCAP and P400-TIP60, in melanoma remains unclear. Here, we show that individual depletion ofSRCAP,P400, andVPS72(YL1)not only results in loss of H2A.Z deposition into chromatin, but also a striking reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a highly coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.
The Myc-Like Mlx Network Impacts Aging and Metabolism
Authors: Wang Huabo , Stevens Taylor , Lu Jie , Roberts Alexander , Land Clinton Van’t , Muzumdar Radhika , Gong Zhenwei , Vockley Jerry , Prochownik Edward V.
Published: November 2023

The “Mlx” and “Myc” Networks share many common gene targets. Just as Myc’s activity depends upon its heterodimerization with Max, the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. We show here that body-wideMlxinactivation, like that ofMyc,accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging-related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability and aging. Whereas “MycKO” mice have an extended lifespan because of a lower cancer incidence, “MlxKO” mice have normal lifespans and a somewhat higher cancer incidence. Like Myc, Mlx, MondoA and ChREBP expression and that of their target genes, deteriorate with age in both mice and humans, underscoring the importance of life-long and balanced cross-talk between the two Networks to maintain normal aging.

Teaser

Inactivation of the Myc-like “Mlx Network” in mice leads to phenotypic and molecular signs of premature aging and a cancer predisposition.
Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking
Authors: Sharp Burt M , Leng Shuangying , Huang Jun , Jones Caroline , Chen Hao
Published: November 2023

Oxycodone abuse begins with prescription oral oxycodone, yet vulnerability factors determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1,4,16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p< 0.001). Each sex increased intake during 16-h vs 4-h sessions (p<2e-16), but a subset of strains dramatically augmented intake at 16-h (p=0.0005). Heritability (h2) of active licks/4-h at increasing oxycodone dose ranged from 0.30-0.53. Under a progressive ratio schedule, breakpoints were strain-dependent (p<2e-16). Cued reinstatement was greater in females (p<0.001). Naive rats were assessed by elevated plus maze (EPM), open field (OF) and novel object interaction (NOI). We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and pleiotropic genes affect anxiety and multiple SA parameters.
Different Diets Modulate the Gut Microbiome Compositions and Promote the Health ofApis mellifera
Authors: Kim Hyun Jee , Maigoro Abdulkadir Yusif , Lee Jeong Hyeon , Frunze Olga , Bilal Mustafa , Kwon Hyung Wook
Published: November 2023

Honey bee (Apis mellifera) health is crucial for honey bee products, and effective pollination and is closely associated with gut bacteria. Various factors such as reduced habitat, temperature, disease, and diet affect the health of honey bees, by disturbing the homeostasis of the gut microbiota. In this study, high-throughput 16S rRNA gene sequencing was used to analyze the gut microbiota ofApis melliferasubjected to seven different diets. The identified microbiota in theApis melliferagut from all the diets consisted ofLactobacillus(62%), followed byRhizobiaceae(21%),Snodgrassella(4%), andErwiniaceae(4%) among other 33 genera. Based on diet types,Lactobacillusa lactic acid bacteria (LAB), dominates the microbiota with the highest relative abundance in AIGT+SAC (91%), AIGT+Soytide (88%), and AIGT+Apple juice (69%) diet groups.BifidobacteriumandCommensalibacterappeared as the second most abundant genera in AIGT+SAC and AIGT+Soytide diet groups, respectively. These bacteria are important markers for honey bee health. Considering the importance of these diets in shaping their host microbiome into a healthy status. Individual honey bee health (IHH) was observed to validate the quality and correlation between the microbiota and honey bee health. The results were consistent, indicating thatApis melliferafed on AIGT+Soytide and AIGT+SAC diet showed the highest health expression level of vitellogenin. The group with 60%Syrup possessingRhizobiaceaeas the dominant taxa showed poor health status. This finding paved the way for establishing a link between gut microbiota and IHH under different diets.
Phylogeny-metabolism dual-directed single-cell genomics for dissecting and mining ecosystem function
Authors: Jing Xiaoyan , Gong Yanhai , Diao Zhidian , Ma Yan , Meng Yu , Chen Jie , Ren Yishang , Li Yinchao , Sun Weihan , Zhang Jia , Ji Yuetong , Liang Yuting , Cong Zhiqi , Li Shengying , Ma Bo , Cui Zhisong , Ma Li , Xu Jian
Published: November 2023

Although microbiome-wide association studies (MWAS) have uncovered many marker organisms for an ecosystem trait, mechanisms of most microbiota-mediated processes remain elusive, due to challenges in validating the markers’in situmetabolic activities and tracing such activities to individual genomes. Here we introduced a phylogeny-metabolism dual-directed single-cell genomics approach called Fluorescence-In-Situ-Hybridization-guided Single-Cell Raman-activated Sorting and Sequencing (FISH-scRACS-Seq). It directly localizes individual cells from target taxon via a FISH probe for marker organism, profiles theirin situmetabolic functions via single-cell Raman spectra, sorts cells of target taxonomy and target metabolism, and produces indexed, high-coverage and precisely-one-cell genomes. From cyclohexane-contaminated seawater, cells representing the MWAS-derived marker taxon of γ-Proteobacteria and that are actively degrading cyclohexanein situwere directly identified via FISH and Raman respectively, then sorted and sequenced for one-cell full genomes. In such aPseudoalteromonas fuligineacell, we discovered a three-component cytochrome P450 system that can convert cyclohexane to cyclohexanolin vitro, representing a previously unknown group of cyclohexane-degrading enzymes and organisms. By culture-independently unveiling enzymes, pathways, genomes and theirin situfunctions specifically for those single-cells with ecological relevance, FISH-scRACS-Seq is a rational and generally applicable approach for dissecting and mining microbiota functions.

Teaser

FISH-scRACS-Seq is a new strategy to dissect microbiota functional mechanism at single-cell resolution.
Menopausal transition alters female skeletal muscle transcriptome
Authors: Juppi Hanna-Kaarina , Korhonen Tia-Marje , Sievänen Tero , Kovanen Vuokko , Kujala Urho M. , Aukee Pauliina , Cronin Neil , Sipilä Sarianna , Karvinen Sira , Laakkonen Eija K.
Published: November 2023

Menopause is associated with unfavorable changes in body composition. Skeletal muscle cells are targets of hormonal regulation and are affected by the interplay between coding and non-coding RNAs. Muscle transcriptome, including messenger-RNA (mRNA), long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) has not previously been studied in women during the menopausal transition. Thus, we took a multi-RNA omics approach to get insight into transcriptome-wide events of menopause. Our study included baseline and follow-up muscle samples from seven early (EarlyMT) and 17 late perimenopausal (LateMT) women transitioning to early postmenopause during the study. Total RNA was sequenced and differential expression (DE) of the transcriptome was investigated. The potential gene functions were investigated with pathway analyses and protein level expression with Western Blot. We found 30 DE mRNA genes in EarlyMT and 19 in LateMT participating in pathways controlling cell death, growth, and interactions with external environment. Lack of protein level changes may indicate a specific role of the regulatory RNAs during menopause. Ten DE lncRNA transcripts were identified but did not result in DE lncRNAs genes. No DE miRNAs were found. Despite the lack of DE findings in regulatory RNAs, we identified putative regulatory networks, likely to be affected by estradiol availability. The changes in gene expression were correlated with observed changes in body composition variables, indicating muscularity and adiposity regulators to be affected by menopausal transition. In essence, the observed DE genes and their regulatory networks may offer novel mechanistic insights on factors affecting body composition during and after menopause.