bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Work-Life Balance on Job Stress and Fatigue in Taxi Drivers
Authors: Göktaş Ayşe
Published: August 2023

Purpose

This is a descriptive study that was conducted to examine the effect of work-life balance on job stress and fatigue in taxi drivers.

Methods

The study included 150 taxi drivers residing in Ankara. As a data collection tool, we used Work-Life Balance, Chalder Fatigue, and Work Stress Scales. We used the Mann-Whitney U test and multiple linear regression analysis.

Results

The model established after multiple linear regression analysis was statistically significant (F[5.142] = 5.442, P < 0.001). A 1-unit increase in the work-life balance variable caused a 2.885-unit decrease in the work stress score and a 0.143-unit decrease in the fatigue score.

Conclusions

We can suggest that taxi drivers who have a work-life balance will be able to participate in social activities in their daily lives, and leisure time activities with family and friends can help motivate individuals more and increase energy.
A Predictive Model of Severe Cytokine Release Syndrome After Coadministration of CD19- and CD22-Chimeric Antigen Receptor T-Cell Therapy in Children With B-Cell Hematological Malignancies Based on Patient-Reported Outcomes
Authors: Zhao Kangjia , Sun Jiwen , He Mengxue , Ruan Haishan , Lin Geng , Shen Nanping
Published: August 2023

Background

Chimeric antigen receptor T-cell therapy–related severe cytokine release syndrome (sCRS) has seriously affected the life safety of patients.

Objective

To explore the influencing factors of sCRS in children with B-cell hematological malignancies and build a risk prediction model.

Methods

The study recruited 115 children with B-cell hematological malignancies who received CD19- and CD22-targeted chimeric antigen receptor T-cell therapy. A nomogram model was established based on symptomatic adverse events and highly accessible clinical variables. The model discrimination was evaluated by the area under the receiver operating characteristic curve. The calibration of our model was evaluated by the calibration curve and Hosmer-Lemeshow test. The bootstrap self-sampling method was used to internally validate.

Results

Thirty-seven percent of the children experienced sCRS. Indicators included in the nomogram were tumor burden before treatment, thrombocytopenia before pretreatment, and the mean value of generalized muscle weakness and headache scores. The results showed that the area under the receiver operating characteristic curve was 0.841, and the calibration curve showed that the probability of sCRS predicted by the nomogram was in good agreement with the actual probability of sCRS. The Hosmer-Lemeshow test indicated that the model fit the data well (χ
2 = 5.759, P = .674). The concordance index (C-index) obtained by internal validation was 0.841 (0.770, 0.912).

Conclusions

The nomogram model constructed has a good degree of discrimination and calibration, which provides a more convenient and visual evaluation tool for identifying the sCRS.

Implications for Practice

Incorporation of patient-reported outcomes into risk prediction models enables early identification of sCRS.
Besieged in the Bronx: Lessons from an in-hospital mass casualty
Authors: Chu Julianne L. , Castaldi Maria , Bridges Kristen , O’Driscoll Kieran M. , Rigdon Amanda R. , Shayesteh Ali , Robinson Sam , Narula Samir , Vemulapalli Pratibha , Gilchrist Brian F.
Published: August 2023

BACKGROUND

An active shooter in a hospital is an emergency extraordinaire. We report a single institution's response to the largest active shooter mass casualty event in American History.

METHODS

Review of notification, flow of prioritized patients, and key elements of the day's dynamic after a hospital attack by a lone gunman were commenced. The review includes outcomes on seven victims and assailants.

RESULTS

“Code Silver” announced: open display of a weapon. Concise, known, and published chain of command implemented. All house staff to the Emergency Department (ED) via text blast. Operating room (OR) notified. Injured to ED, then triaged to OR. Armed NYPD stationed throughout OR. Senior surgeons controlled key triage during attack with flow controlled from the ED and OR control desk. One fatality plus shooter.

CONCLUSION

Success favors the prepared. The response to attack, readiness of medical personnel, mitigation, and recovery have brought the following recommendations: (1) single entrance access; (2) armed, professional guards at all entrances; (3) camouflage metal detectors; (4) mandatory, recurrent hospital-wide active shooter training, mock, and table top; (5) published physician chain of command; (6) intercom code system known to all hospital personnel indicating a weapon is openly displayed; (7) a “no fly” list of former employees who are prohibited on premises; (8) stop the bleed training with kits on every floor; (9) one voice, one face to disseminate information.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level I.
Febuxostat, a xanthine oxidase inhibitor, regulated long noncoding RNAs and protected the brain after intracerebral hemorrhage
Authors: Zhang Chenyu , Tang Linqiao , Zhang Ying , Wang Qi , Wang Xueyan , Bai Yang , Fang Zhenwei , Zhang Tiejun , Xu Ting , Li Yuwen
Published: August 2023

Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease and is associated with a high global health burden. Long noncoding RNAs are involved in the pathological damage of ICH. Febuxostat, one of the xanthine oxidase inhibitors, is commonly used in the treatment of hyperuricemia and has been studied in different pathological processes, and its protective effects have been proven in different organs. This study was conducted to investigate whether febuxostat protects brain via regulating long noncoding RNAs after ICH. The modified neurological severity score, wire hanging test, Evans blue perfusion and immunofluorescence were performed to test the protective effects of febuxostat in a mouse model of ICH. Whole transcriptome sequencing was conducted to identify the lncRNAs affected by febuxostat and their functions were analyzed. Febuxostat ameliorated behavioral abnormalities and protected the blood-brain barrier after ICH. Fifteen lncRNAs regulated by febuxostat after ICH were detected. These 15 lncRNAs were associated with 83 gene ontology items. In total, 35 genes, 15 mRNAs and 202 miRNAs were regarded as potential targets for the 15 lncRNAs; 183 co-expressed genes were identified for these 15 lncRNAs and the co-expression network was constructed. Potential binding between lncRNAs and mRNAs was also studied. Enrichment analysis revealed that the functions of the 15 lncRNAs were related to maintaining the blood-brain barrier. This study demonstrated febuxostat protected brain after ICH. Fifteen lncRNAs were regulated and were associated with the effects of febuxostat on BBB integrity after ICH.
Intrathecal rapamycin attenuates the mechanical hyperalgesia of paclitaxel-induced peripheral neuropathy in mice
Authors: Lu Ze-Peng , Zou Jia-Qi , Lian Wan-Yi , Lei Hong-Yi , Xu Shi-Yuan
Published: August 2023

Paclitaxel is an extensively used chemotherapy antitumor drug and paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common side effect. Rapamycin, originally used as an adjuvant drug for chemotherapy, has recently been found to possess potential neuroprotective activities. Our purposes of this study are to verify the effect of rapamycin on PIPN, which contributes to a new target for PIPN treatment. Mice were given paclitaxel or rapamycin with different injection methods. Paw withdrawal threshold was tested at different time points for mechanical sensitivity assessment. Administration of paclitaxel, both 2 mg/kg and 5 mg/kg, could induce mechanical hypersensitivity. 0.01 mg intrathecal injection of rapamycin showed the best effect on attenuate the mechanical hyperalgesia of PIPN. Intrathecal injection of only rapamycin would not induce the mechanical hyperalgesia while when rapamycin and paclitaxel were used together the mechanical hyperalgesia induced by paclitaxel could be attenuated. Paclitaxel could induce mechanical hyperalgesia in mice and rapamycin could attenuate such mechanical hyperalgesia of PIPN.
A cross-sectional study in critically ill patients affected by COVID-19 in an intensive care unit: would Acinetobacter baumannii resistant to carbapenems be the biggest villain?
Authors: Rocha Yamashita Sayuri , Milani Martins Vera Lucia , Pires Maciel Elves Anderson , Azeredo Francine Johansson
Published: August 2023

Aim: to describe cases of infection of Acinetobacter baumannii (A. baumannii) in critically ill patients affected by COVID-19, admitted to an intensive care unit (ICU), using dexamethasone. Methodology: Cross-sectional study conducted on patients admitted to the intensive care unit COVID-19 survey among hospitalized patients from November 2020 to March 2021. Setting: large hospital, reference for caring for patients with COVID-19 in Bahia (Brazil). Patients: a convenience sample of 22 patients admitted to the COVID ICU signed the consent form agreeing to participate in the study. Three patients were excluded for having decided to participate without signing the term. Results: Of the 22 patients listed, 45% (10) had blood infection or mechanical ventilation-associated pneumonia by A. baumannii in blood cultures and/or tracheal aspirate secretion. We observed that there is a moderate correlation between the length of stay and infection by A. baumannii (Spearman's ρ; 0.592; p-value<0.005) and a strong correlation between the number of days on mechanical ventilation and infection by these bacteria (Spearman's ρ; 0.740; p-value<0.001). This percentage is higher than the value of 0.62% of infection by A. baumannii in this ICU in the same period of the year before COVID-19 (p-value<0.0001). Conclusions: Hospitals that receive patients with COVID-19 may be vulnerable to outbreaks of multi-drug resistant organisms, such as A. baumannii. It is worth reflecting on the care and operational practices in handling these patients, especially in isolation and restriction measures for those from other nosocomial areas.
Challenges in the diagnosis and management of atypical fungal keratitis during the COVID-19 pandemic: a case series
Authors: Ali Dideeya , Vijayan Ajith , Shenoy Kashinatha , Antony Ann Tresa , Ramachandran Reshmi
Published: August 2023

Fungal keratitis is a time-sensitive ocular infection that often requires a high index of suspicion followed by intensive medical/surgical interventions to achieve a successful clinical outcome. COVID-19 pandemic-related restrictions, necessitated the modification of conventional protocols and guidelines associated with the treatment of keratomycosis. We report four cases of atypical fungal keratitis with poorly differentiated clinical characteristics. The challenges faced during their management were (1) the dilemma of clinically differentiating fungal (Scedosporium and Purpureocillium lilacinum) and bacterial keratitis; (2) treatment of Scedosporium and Trichosporon keratitis with natamycin monotherapy; (3) mixed infection of Candida albicans and Aureobasidium pullulans and continuing medications before rescraping the corneal ulcer against the recommended treatment guidelines; (4) phenotypic identification and differentiation among morphologically resembling fungi; and (5) decision making arising out of disparities between KOH and fungal culture results. Three patients responded well to conservative treatments. The fourth patient underwent therapeutic keratoplasty but was lost to follow-up due to travel-related pandemic restrictions. This case series seeks to broaden the clinician’s knowledge of rare and emerging moulds as presumptive aetiologies of keratomycosis. It also intends to emphasize the significance of early microbiological investigations, (direct microscopy and culture), in resource-limited settings, for initiating empirical treatment for a better visual prognosis.
Alternate inks for arbuscular mycorrhizal root staining
Authors: Wilkes Thomas I
Published: August 2023

Alternate methods for root staining of arbuscular mycorrhizal (AM) fungi have recently gained more attention for the reduction of hazard exposure to the user. Sheaffer® blue ink has been employed for such an identification and quantification, having shown and increased degree of image clarity. However, sourcing Sheaffer® blue ink is becoming problematic, leading to the need to find alternative inks that are readily available. Parker® ink is a well-known brand, providing comparable colour option to Sheaffer®. Two Parker® inks, blue and washable blue, were employed alongside Sheaffer® blue for comparative AM fungal root staining. From quantified AM fungal vesicles and arbuscles, along with the degree of stained image clarity under microscopy, none of the inks utilised for this comparison produce a significantly (P=0.97) different AM fungal quantification or change in image clarity. Therefore, results of the present communication suggest that Parker® blue and washable blue inks are alternative ink stains for the viewing and quantification of AM fungi in host cortical root tissues.
Benchmark Pathology Report Text Corpus with Cancer Type Classification
Authors: Kefeli Jenna , Tatonetti Nicholas
Published: August 2023

In cancer research, pathology report text is a largely un-tapped data source. Pathology reports are routinely generated, more nuanced than structured data, and contain added insight from pathologists. However, there are no publicly-available datasets for benchmarking report-based models. Two recent advances suggest the urgent need for a benchmark dataset. First, improved optical character recognition (OCR) techniques will make it possible to access older pathology reports in an automated way, increasing data available for analysis. Second, recent improvements in natural language processing (NLP) techniques using AI allow more accurate prediction of clinical targets from text. We apply state-of-the-art OCR and customized post- processing to publicly available report PDFs from The Cancer Genome Atlas, generating a machine-readable corpus of 9,523 reports. We perform a proof-of-principle cancer-type classification across 32 tissues, achieving 0.992 average AU-ROC. This dataset will be useful to researchers across specialties, including research clinicians, clinical trial investigators, and clinical NLP researchers.
The Relationship of Duffy Gene Polymorphism, High Sensitivity C-Reactive Protein, and Long-term Outcomes
Authors: Ha Edward T. , Taylor Kent D. , Raffield Laura M , Briggs Matt , Yee Aaron , Elemento Olivier , Parikh Manish , Peterson Stephen J. , Frishman William , Gerszten Robert E. , Wilson James G. , Kelsey Karl , Tahir Usman A. , Reiner Alex , Auer Paul , Seeman Teresa , Rich Stephen S. , Carson April P. , Post Wendy S. , Rotter Jerome I. , Aronow Wilbert S.
Published: August 2023

Background

Black adults have higher incidence of all-cause death and worse cardiovascular outcomes when compared to other populations. The Duffy chemokine receptor is not expressed in a large majority of Black adults and the clinical implications of this are unclear.

Methods

Here, we investigated the relationship of Duffy receptor status, high-sensitivity C-reactive protein (hs-CRP), and long-term cardiovascular outcomes in Black members of two contemporary, longitudinal cohort studies (the Jackson Heart Study and Multi-Ethnic Study of Atherosclerosis). Data on 4,307 Black participants (2,942 Duffy null and 1,365 Duffy receptor positive, as defined using Single Nucleotide Polymorphism (SNP) rs2814778) were included in this analysis.

Results

Duffy null was not independently associated with elevated levels of serum hs-CRP levels once conditioning for knownCRPlocus alleles in linkage disequilibrium with the Duffy gene. Duffy null status was not found to be independently associated with higher incidence of all-cause mortality or secondary outcomes after adjusting for possible confounders in Black participants.

Conclusions

These findings suggest that increased levels of hs-CRP found in Duffy null individuals is due to co-inheritance of CRP alleles known to influence circulating levels hs-CRP and that Duffy null status was not associated with worse adverse outcomes over the follow-up period in this cohort of well-balanced Black participants.
Much more than a name change: Impact of the new steatotic liver disease nomenclature on clinical algorithms and disease classification in U.S. adults and adolescents
Authors: Ma Ning , Bansal Meena , Chu Jaime , Branch Andrea D.
Published: August 2023

Background and Aims:

The newly proposed nomenclature for steatotic liver diseases (SLD) aims to reduce the stigma associated with “non-alcoholic fatty liver disease” (NAFLD), increase awareness, and provide a framework for delineating pathogenic pathways.

Approach and Results:

We projected the new nomenclature’s diagnostic scheme onto National Health and Nutrition Examination Survey (NHANES) data and determined SLD prevalence, fibrosis risk factors, subtypes, and consistency with previous classifications. Steatosis grade and fibrosis stage were estimated from vibration controlled transient elastography (VCTE). At a threshold of 240 dB/m, 62.1% [95% confidence interval (CI), 59.8-64.3%] of adults (≥ 20 years) and 30.5% (95% CI, 27.1-34.0%) of adolescents (12-19 years) had SLD. By American Gastroenterological Association criteria, 19.3 million (95% CI, 15.8-22.8) adults with SLD qualify for hepatology referral. Over 98% of adults but only 85% of adolescents with NAFLD met criteria for definite MASLD. Significant fibrosis (≥ 8.6 kPa) occurred in 13.5 million (95% CI, 10.9-16.2) adults with MASLD; risk factors varied by race and ethnicity. Significant fibrosis occurred in over 1.5 million adults without any identified LD and was associated with lead (Pb) exposure, odds ratio = 3.89 (95% CI, 2.00-7.56).

Conclusions:

The overarching term, SLD, changes the diagnostic algorithm and creates an umbrella classification that highlights the extraordinary prevalence of liver steatosis. The more precise nomenclature establishes a valuable patient-centric platform for research and clinical care, clarifying risk groups and risk factors, including adolescents with NAFLD but without definite MASLD and adults without SLD in whom toxic exposures may increase fibrosis risk.
SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection
Authors: Richards Alexsia , Khalil Andrew , Friesen Max , Whitfield Troy W. , Gao Xinlei , Lungjangwa Tenzin , Kamm Roger , Wan Zhengpeng , Gehrke Lee , Mooney David , Jaenisch Rudolf
Published: August 2023

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly SMCs, are a susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterize the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, PCs, and ECs. We observe that infected SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we show human ECs exposed to the secretome of infected SMCs produce hemostatic factors that contribute to vascular dysfunction, despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level.
Deep learning methods in metagenomics: a review
Authors: Roy Gaspar , Prifti Edi , Belda Eugeni , Zucker Jean-Daniel
Published: August 2023

The ever-decreasing cost of sequencing and the growing potential applications of metagenomics have led to an unprecedented surge in data generation. One of the most prevalent applications of metagenomics is the study of microbial environments, such as the human gut. The gut microbiome plays a crucial role in human health, providing vital information for patient diagnosis and prognosis. However, analyzing metagenomic data remains challenging due to several factors, including reference catalogs, sparsity, and compositionality. Deep learning (DL) enables novel and promising approaches that complement state-of-the-art microbiome pipelines. DL-based methods can address almost all aspects of microbiome analysis, including novel pathogen detection, sequence classification, patient stratification, and disease prediction. Beyond generating predictive models, a key aspect of these methods is also their interpretability. This article reviews deep learning approaches in metagenomics, including convolutional networks (CNNs), autoencoders, and attention-based models. These methods aggregate contextualized data and pave the way for improved patient care and a better understanding of the microbiome’s key role in our health.

Author summary

In our study, we look at the vast world of research in metagenomics, the study of genetic material from environmental samples, spurred by the increasing affordability of sequencing technologies. Our particular focus is the human gut microbiome, an environment teeming with microscopic life forms that plays a central role in our health and well-being. However, navigating through the vast amounts of data generated is not an easy task. Traditional methods hit roadblocks due to the unique nature of metagenomic data. That’s where deep learning (DL), a today well known branch of artificial intelligence, comes in. DL-based techniques complement existing methods and open up new avenues in microbiome research. They’re capable of tackling a wide range of tasks, from identifying unknown pathogens to predicting disease based on a patient’s unique microbiome. In our article, we provide a very comprehensive review of different DL strategies for metagenomics, including convolutional networks, autoencoders, and attention-based models. We are convinced that these techniques significantly enhance the field of metagenomic analysis in its entirety, paving the way for more accurate data analysis and, ultimately, better patient care. The PRISMA augmented diagram of our review is illustrated inFig 1.
Many morphs: parsing gesture signals from the noise
Authors: Mielke Alexander , Badihi Gal , Graham Kirsty E. , Grund Charlotte , Hashimoto Chie , Piel Alex K. , Safryghin Alexandra , Slocombe Katie E. , Stewart Fiona , Wilke Claudia , Zuberbühler Klaus , Hobaiter Catherine
Published: August 2023

Parsing signals from noise is a general problem for signallers and recipients, as well as for researchers studying communicative systems. Substantial research efforts have been invested in comparing how other species encode information and meaning in their signals, and how signalling is structured. However, our ability to do so depends on identifying and discriminating signals that represent meaningful units of analysis. Early approaches to defining signal repertoires applied top- down approaches, classifying cases into predefined signal types. Recently, more labour-intensive methods have taken a bottom-up approach describing the features of each signal in detail and clustering cases into types based on patterns of similarity between them in multi-dimensional feature-space that were previously undetectable. Nevertheless, it remains essential to assess whether the resulting repertoires are composed of relevant units from the perspective of the species using them, and redefining repertoires when additional data makes more detailed analyses feasible. In this paper we provide a framework that takes data from the largest set of wild chimpanzee (Pan troglodytes) gestures currently available, splitting gesture types at a fine scale based on modifying features of gesture expression and then determining whether this splitting process increases the information content of the communication system. Our method allows different features of interest to be incorporated into the splitting process, providing substantial future flexibility across - for example - species, populations, and levels of signal granularity. In doing so we provide a powerful tool allowing researchers interested in gestural communication to establish repertoires of relevant units for subsequent analyses within and between systems of communication.
Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson’s Disease Mouse Model
Authors: Choi In Sun , Kim Jinmo , Choi Joon Ho , Choi Ji-Woong , Rah Jong-Cheol
Published: August 2023

The subthalamic nucleus (STN) is important in halting ongoing behaviors, referred to as stop-signal responses. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and optogenetic activation of these neurons inhibits impulsive actions in rodents. High-frequency electrical stimulation of the STN effectively treats motor symptoms of Parkinson’s disease (PD), yet its underlying circuit mechanisms are unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation, during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study unveils excessive excitability and suppressive motor control through M2-STN synapses in the PD mouse model. Antidromic excitation of M2 neurons during deep brain stimulation of the STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulation’s therapeutic effects in PD. Targeting M2-STN synapses may be useful for future therapeutic strategies.

Significance Statement

Our study provides insight into the mechanisms underlying motor impairment in Parkinson’s disease (PD) and the therapeutic effect of deep brain stimulation (DBS). By elucidating the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in modulating the hyperexcitability of M2 neurons, we identify potential targets for future PD treatment strategies. Understanding the excessive excitability and suppressive motor control through M2-STN synapses in PD mouse models contributes to our knowledge of circuit-level dynamics underlying DBS effects. These findings have significant implications for improving motor symptoms and advancing the development of more precise and effective interventions for PD patients.

Highlights

STN-projecting M2 neurons show increased burst firing in PD mice.

High-frequency stimulation relieves M2 hyperexcitability and motor symptoms.

Reduction in M2 hyperexcitability by DBS linked to normalized Ih.

ZD7288 infusion in M2 replicates high-frequency stimulation effects.

Targeted modulation of M2 neurons may alleviate PD symptoms.
The Moa the Merrier: Resolving When the Dinornithiformes Went Extinct
Authors: Foxon Floe
Published: August 2023

The Moa (Aves: Dinornithiformes) are an extinct group of the ratite clade from New Zealand. The overkill hypothesis asserts that the first New Zealand settlers hunted the Moa to extinction by 1450 CE, whereas the staggered survival hypothesis allows for Moa survival until after Europeans began to arrive on New Zealand. Alleged Moa sightings post-1450 CE may shed light on these competing hypotheses. A dataset of 97 alleged Moa sightings from circa 1675 CE to 1993 CE was constructed, with sightings given subjective quality ratings corresponding to various statistical probabilities. Cumulative probabilities of Moa persistence were calculated with a conservative survival model using these probabilistic sighting-records; a method recently applied to sightings of the Thylacine. Cumulative persistence probability fell sharply after 1408 CE, and across pessimistic and optimistic variations of the model, it was more likely than not that the Moa were extinct by 1770 CE. Probabilistic sighting-record models favour the overkill hypothesis, and give very low probabilities of Moa persistence around the time of European arrival. Eyewitness data on Moa sightings are amenable to scientific study, and these methods may be applied to similar animals.
Genetic Characterization of Glyoxalase Pathway in Oral Streptococci and its Contribution to Interbacterial Competition
Authors: Zeng Lin , Noeparvar Payam , Burne Robert A , Glezer Benjamin S.
Published: August 2023

Substantial quantities of Reactive Electrophile Species (RES), including methylglyoxal and glyoxal, are generated by microbes and humans. To understand the impact of RES on oral microbial homeostasis, genetic analyses were performed on the glyoxalase pathway inStreptococcus mutans(SMU) andStreptococcus sanguinis(SSA). Loss of glyoxalase I (LguL), which catalyzes the rate-limiting reaction in RES degradation, reduced methylglyoxal and glyoxal tolerance to a far greater extent in SMU than in SSA, decreasing the competitiveness of SMU over SSA in planktonic cultures. MICs showed an overall greater RES tolerance by SMU than SSA; a finding consistent with the ability of methylglyoxal to induce the expression oflguLin SMU, but not in SSA. Computational analysis identified a novel paralogue of LguL in most streptococci represented by SMU.1112c in SMU. ΔSMU.1112c showed a minor decrease in methylglyoxal tolerance under certain conditions, but a significant growth defect on fructose; a phenotype reversed by the deletion of a fructose-1-phosphate-generating sugar: phosphotransferase system or addition of glutathione (GSH) to the medium. Further, deletion of the glucose-PTS in SMU increased RES tolerance partly through enhanced expression of the pyruvate-dehydrogenase complex. Consistent with the requirement of GSH for methylglyoxal detoxification, deletion of glutathione synthetase (gshAB) in SMU significantly reduced RES resistance. This study reveals the critical roles of RES in fitness and interbacterial competition and the effects of PTS in modulating RES metabolism. The fact that RES may impact the pathogenic potential of the oral microbiome via differential effects on beneficial and pathogenic species warrants further investigation.

Importance

As highly reactive byproducts of sugar metabolism, very little is known regarding the contribution of methylglyoxal or related aldehyde compounds to oral health. The need to better understand the influence of these reactive electrophile species (RES) to microbial physiology and ecology is made more urgent by the widespread condition of hyperglycemia in humans, which is associated with elevated RES levels. Our study showed a significantly greater ability of a major caries pathobiont,Streptococcus mutans, to tolerate methylglyoxal and glyoxal than many commensal oral streptococci. Genetic analysis of methylglyoxal degradation in the pathobiont and commensals identified significant differences in genetic structure and gene regulation patterns that could contribute to differential fitness by constituents of the dental microbiota and ecologic shift in the presence of RES.
Benchmarking informatics approaches for virus discovery: Caution is needed when combiningin silicoidentification methods
Authors: Hegarty Bridget , Riddell V James , Bastien Eric , Langenfeld Kathryn , Lindback Morgan , Saini Jaspreet S. , Wing Anthony , Zhang Jessica , Duhaime Melissa
Published: August 2023

Background

The identification of viruses from environmental metagenomic samples using informatics tools has offered critical insights in microbiome studies. However, it remains difficult for researchers to know for their specific study which tool(s) and settings are best suited to maximize capture of viruses while minimizing false positives. Studies are increasingly combining multiple tool outputs attempting to recover more viruses, but no combined approach has been benchmarked for accuracy. Here, we benchmarked 63 viral identification ‘rulesets’ against mock metagenomes composed of publicly available viral, bacterial, archaeal, fungal, and protist sequences. These rulesets are based on combinations of four single-tool rules and two multi-tool tuning rules. We applied these rulesets to various aquatic metagenomes and filtering strategies to evaluate the impact of habitat and viral enrichment on individual and combined tool performance. We provide a packaged pipeline for researchers that want to replicate our process.

Results

We found that combining rules increased viral recall, but at the expense of increased false positives. Six of the 63 combinations tested had equivalent accuracies to the highest one (MCC=0.77, padj≥ 0.05). All of the six high accuracy rulesets included VirSorter2, five included our “tuning removal” rule, and no high performing rulesets used more than four of our six rules. DeepVirFinder, VIBRANT, and VirSorter were each found once in these high accuracy rulesets, but never in combination with each other. Our validation suggests that the MCC plateau at 0.77 is caused by inaccurate labeling of the data that viral identification tools rely on for training and validation. In the aquatic metagenomes, our “highest MCC” ruleset identified a higher proportion of viral sequences in the virus-enriched samples (44-46%) than the non-enriched, cellular metagenomes (7-19%).

Conclusion

While improved algorithms may lead to more accurate viral identification tools, this should be done in tandem with curating accurately labeled viral gene and sequence databases. For most applications, we recommend the use of the ruleset that uses VirSorter2 and our empirically derived tuning removal rule. By providing a rigorous overview of the behavior ofin silicoviral identification strategies, our findings guide the use of existing viral identification tools and offer a blueprint for feature engineering of new tools that will lead to higher-confidence viral discovery in microbiome studies.
Assessment of bovine cortical bone fracture behavior using impact microindentation as a surrogate of fracture toughness
Authors: Jahani Babak , Vaidya Rachana , Jin James M. , Aboytes Donald A. , Broz Kaitlyn S. , Khrotapalli Siva , Pujari Bhanuteja , Baig Walee M. , Tang Simon Y.
Published: August 2023

The fracture behavior of bone is critically important for assessing its mechanical competence and ability to resist fractures. Fracture toughness, which quantifies a material’s resistance to crack propagation under controlled geometry, is regarded as the gold standard for evaluating a material’s resistance to fracture. However properly conducting this test requires access to calibrated mechanical load frames the destruction of the bone samples, making it impractical for obtaining clinical measurement of bone fracture. Impact microindentation offers a potential alternative by mimicking certain aspects of fracture toughness measurements, but its relationship with mechanistic fracture toughness remains unknown. In this study, we aimed to compare measurements of notched fracture toughness and impact microindentation in fresh and boiled bovine bone. Skeletally mature bovine bone specimens (n=48) were prepared, and half of them were boiled to denature the organic matrix, while the other half remained preserved in frozen conditions. Notched fracture toughness tests were conducted on all samples to determine Initiation toughness (KIC), and an impact microindentation test using the OsteoProbe was performed to obtain the Bone Material Strength index. Boiling the bone samples resulted increased the denatured collagen without affecting mineral density or porosity. The boiled bones also showed significant reduction in both KIC(p < 0.0001) and the average Bone Material Strength index (p < 0.0001), leading to impaired resistance of bone to crack propagation. Remarkably, the average Bone Material Strength index exhibited a high correlation with KIC(r = 0.86; p < 0.001). The ranked order difference analysis confirmed excellent agreement between the two measures. This study provides the first evidence that impact microindentation could serve as a surrogate measure for bone fracture behavior. The potential of impact microindentation to non-destructively assess bone fracture resistance could offer valuable insights into bone health without the need for elaborate testing equipment and sample destruction.
Gas tunnel engineering of prolyl hydroxylase reprograms hypoxia signaling in cells
Authors: Windsor Peter , Ouyang Haiping , da Costa Joseph A. G. , Damodaran Anoop Rama , Chen Yue , Bhagi-Damodaran Ambika
Published: August 2023

Cells have evolved intricate mechanisms for recognizing and responding to changes in oxygen (O2) concentrations. Here, we have reprogrammed cellular hypoxia (low O2) signaling via gas tunnel engineering of prolyl hydroxylase 2 (PHD2), a non-heme iron dependent O2sensor. Using computational modeling and protein engineering techniques, we identify a gas tunnel and critical residues therein that limit the flow of O2to PHD2’s catalytic core. We show that systematic modification of these residues can open the constriction topology of PHD2’s gas tunnel. Using kinetic stopped-flow measurements with NO as a surrogate diatomic gas, we demonstrate up to 3.5-fold enhancement in its association rate to the iron center of tunnel-engineered mutants. Our most effectively designed mutant displays 9-fold enhanced catalytic efficiency (kcat/KM= 830 ± 40 M-1s-1) in hydroxylating a peptide mimic of hypoxia inducible transcription factor HIF-1α, as compared to WT PHD2 (kcat/KM= 90 ± 9 M-1s-1). Furthermore, transfection of plasmids that express designed PHD2 mutants in HEK-293T mammalian cells reveal significant reduction of HIF-1α and downstream hypoxia response transcripts under hypoxic conditions of 1% O2. Overall, these studies highlight activation of PHD2 as a new pathway to reprogram hypoxia responses and HIF signaling in cells.
Rechargeable Biomineral Induced by Sulfate Reducing BacteriumCupidesulfovibriosp. HK-II
Authors: Arashi Yui , Mochihara Hiroki , Kubota Hiroko , Suzuki Kei , Chiba Yusuke , Kato Yutaka , Kogure Toshihiro , Moriuchi Ryota , Dohra Hideo , Tashiro Yosuke , Futamata Hiroyuki
Published: August 2023

A black precipitate produced by a sulfate reducing bacteriumCupidesulfovibriosp. strain HK was investigated with multidisciplinary methods. X-ray diffraction (XRD) analysis revealed that the black precipitate was mackinawite. Cyclic voltammetry analysis showed the obvious redox peaks, and the biogenic mackinawite exhibited rechargeable properties. XRD analyses showed that the form of the rechargeable biogenic mackinawite (RBM-II) was changed by discharge and recharge treatments: Field-emission transmission electron microscope analyses revealed that lepidocrocite and amorphous iron oxide were appeared from mackinawite on discharged condition, and the three kinds of minerals were intermingled via the rechargeable treatments. Physicochemical parameters were changed regularly under the treatments, suggesting that discharge would be occurred by iron oxidation and sulfur reduction, andvice versa. These results indicated that dynamics of sulfur is important key process in rechargeable mechanism, supporting that a part of mackinawite was transformed to lepidocrocite and iron oxides, andvice versa. Microbial fuel cells (MFCs) equipped with lactate, strain HK-II and anode including RBM-II consumed lactate even under opened circuit conditions, after which MFCs generated higher current density at re-closed circuit conditions. These results demonstrated that the biogenic mackinawite is one of rechargeable materials and would play important roles in geomicrobiological reactions and biotechnology.
Mathematical Modeling of Field Cancerization through the Lens of Cancer Behavioral Ecology
Authors: Bukkuri Anuraag , Adler Frederick R.
Published: August 2023

Field cancerization is a process in which a normal tissue is replaced with pre-cancerous but histologically normal tissue. This transformed field can give rise to malignancy and contribute to tumor relapse. In this paper, we create a mathematical model of field cancerization from the perspective of cancer behavioral ecology. In our model, field cancerization arises from a breakdown in signaling integrity and control, and investigate implications for acute wounding, chronic wounding, aging, and therapeutic interventions. We find that restoration of communication networks can lead to cancer regression in the context of acute injury. Conversely, long term loss of controls, such as through chronic wounding or aging, can promote oncogenesis.

These results are paralleled in therapeutic interventions: those that simply target cells in cancerous states may be less effective than those that reestablish signaling integrity. Viewing cancer as a corruption of communication systems rather than as a corruption of individual cells may lead to novel approaches for understanding and treating this disease.
Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming
Authors: Murphy Sean , Rahmy Sharif , Gan Dailin , Zhu Yini , Manyak Maxim , Li Jun , Lu Xuemin , Lu Xin
Published: August 2023

Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8+T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.
The synapsin-dependent vesicle cluster is crucial for presynaptic plasticity at a glutamatergic synapse in male mice
Authors: Bruentgens Felicitas , Velasquez Laura Moreno , Stumpf Alexander , Parthier Daniel , Breustedt Jörg , Benfenati Fabio , Milovanovic Dragomir , Schmitz Dietmar , Orlando Marta
Published: August 2023

Synapsins are highly abundant presynaptic proteins that play a crucial role in neurotransmission and plasticity via the clustering of synaptic vesicles. The synapsin III isoform is usually downregulated after development, but in hippocampal mossy fiberboutonsit persists in adulthood. Mossy fiberboutonsexpress presynaptic forms of short- and long-term plasticity, which are thought to underlie different forms of learning. Previous research on synapsins at this synapse focused on synapsin isoforms I and II. Thus, a complete picture regarding the role of synapsins in mossy fiber plasticity is still missing. Here, we investigated presynaptic plasticity at hippocampal mossy fiberboutonsby combining electrophysiological field recordings and transmission electron microscopy in a mouse model lacking all synapsin isoforms. We found decreased short-term plasticity - i.e. decreased facilitation and post-tetanic potentiation - but increased long-term potentiation in male synapsin triple knockout mice. At the ultrastructural level, we observed more dispersed vesicles and a higher density of active zones in mossy fiberboutonsfrom knockout animals. Our results indicate that all synapsin isoforms, including synapsin III, are required for fine regulation of short- and long-term presynaptic plasticity at the mossy fiber synapse.

Significance statement

Synapsins cluster vesicles at presynaptic terminals and shape presynaptic plasticity at giant hippocampal mossy fiberboutons. Deletion of all synapsin isoforms results in decreased short- but increased long-term plasticity.
Partial alignment of multislice spatially resolved transcriptomics data
Authors: Liu Xinhao , Zeira Ron , Raphael Benjamin J.
Published: August 2023

Spatially resolved transcriptomics (SRT) technologies measure messenger RNA (mRNA) expression at thousands of locations in a tissue slice. However, nearly all SRT technologies measure expression in two-dimensional (2D) slices extracted from a 3D tissue, thus losing information that is shared across multiple slices from the same tissue. Integrating SRT data across multiple slices can help recover this information and improve downstream expression analyses, but multislice alignment and integration remains a challenging task. Existing methods for integrating SRT data either do not use spatial information or assume that the morphology of the tissue is largely preserved across slices, an assumption that is often violated because of biological or technical reasons. We introduce PASTE2, a method forpartialalignment and 3D reconstruction of multislice SRT data sets, allowing only partial overlap between aligned slices and/or slice-specific cell types. PASTE2 formulates a novelpartialfused Gromov-Wasserstein optimal transport problem, which we solve using a conditional gradient algorithm. PASTE2 includes a model selection procedure to estimate the fraction of overlap between slices, and optionally uses information from histological images that accompany some SRT experiments. We show on both simulated and real data that PASTE2 obtains more accurate alignments than existing methods. We further use PASTE2 to reconstruct a 3D map of gene expression in aDrosophilaembryo from a 16 slice Stereo-seq data set. PASTE2 produces accurate alignments of multislice data sets from multiple SRT technologies, enabling detailed studies of spatial gene expression across a wide range of biological applications.