bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of transcript regions and amino acid choice in nucleosome positioning
Authors: Yadav Manish , Zuiddam Martijn , Schiessel Helmut
Published: September 2023

Eukaryotic DNA is organized and compacted in a string of nucleosomes, DNA-wrapped protein cylinders. The positions of nucleosomes along DNA are not random but show well-known base pair sequence preferences that result from the sequence-dependent elastic and geometric properties of the DNA double helix. Here, we focus on DNA around transcription start sites, which are known to typically attract nucleosomes in multicellular life forms through their high GC content. We aim to understand how these GC signals, as observed in genome-wide averages, are produced and encoded through different genomic regions (mainly 5′ UTRs, coding exons, and introns). Our study uses a bioinformatics approach to decompose the genome-wide GC signal into between-region and within-region signals. We find large differences in GC signal contributions between vertebrates and plants and, remarkably, even between closely related species. Introns contribute most to the GC signal in vertebrates, while in plants the exons dominate. Further, we find signal strengths stronger on DNA than on mRNA, suggesting a biological function of GC signals along the DNA itself, as is the case for nucleosome positioning. Finally, we make the surprising discovery that both the choice of synonymous codons and amino acids contribute to the nucleosome positioning signal.
Alternative splicing impacts microRNA regulation within coding regions
Authors: Hackl Lena Maria , Fenn Amit , Louadi Zakaria , Baumbach Jan , Kacprowski Tim , List Markus , Tsoy Olga
Published: September 2023

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind to target sites in different gene regions and regulate post-transcriptional gene expression. Approximately 95% of human multi-exon genes can be spliced alternatively, which enables the production of functionally diverse transcripts and proteins from a single gene. Through alternative splicing, transcripts might lose the exon with the miRNA target site and become unresponsive to miRNA regulation. To check this hypothesis, we studied the role of miRNA target sites in both coding and non-coding regions using six cancer data sets from The Cancer Genome Atlas (TCGA) and Parkinson’s disease data from PPMI. First, we predicted miRNA target sites on mRNAs from their sequence using TarPmiR. To check whether alternative splicing interferes with this regulation, we trained linear regression models to predict miRNA expression from transcript expression. Using nested models, we compared the predictive power of transcripts with miRNA target sites in the coding regions to that of transcripts without target sites. Models containing transcripts with target sites perform significantly better. We conclude that alternative splicing does interfere with miRNA regulation by skipping exons with miRNA target sites within the coding region.
Radio-pathomic approaches in pediatric neuro-oncology: Opportunities and challenges
Authors: Familiar Ariana M , Mahtabfar Aria , Fathi Kazerooni Anahita , Kiani Mahsa , Vossough Arastoo , Viaene Angela , Storm Phillip B , Resnick Adam C , Nabavizadeh Ali
Published: September 2023

With medical software platforms moving to cloud environments with scalable storage and computing, the translation of predictive artificial intelligence (AI) models to aid in clinical decision-making and facilitate personalized medicine for cancer patients is becoming a reality. Medical imaging, namely radiologic and histologic images, has immense analytical potential in neuro-oncology, and models utilizing integrated radiomic and pathomic data may yield a synergistic effect and provide a new modality for precision medicine. At the same time, the ability to harness multi-modal data is met with challenges in aggregating data across medical departments and institutions, as well as significant complexity in modeling the phenotypic and genotypic heterogeneity of pediatric brain tumors. In this paper, we review recent pathomic and integrated pathomic, radiomic, and genomic studies with clinical applications. We discuss current challenges limiting translational research on pediatric brain tumors and outline technical and analytical solutions. Overall, we propose that to empower the potential residing in radio-pathomics, systemic changes in cross-discipline data management and end-to-end software platforms to handle multi-modal data sets are needed, in addition to embracing modern AI-powered approaches. These changes can improve the performance of predictive models, and ultimately the ability to advance brain cancer treatments and patient outcomes through the development of such models.
The essentiality of money in a trading post economy with random matching
Authors: Marchesiani Alessandro
Published: September 2023

This article studies how the structure of centralized markets can affect efficient allocation in anonymous decentralized trades. In line with previous studies, we show that efficiency in decentralized markets can be sustained in a moneyless finite-number-of-agents setting if agents are patient enough and the price is observed with noise. We additionally show that, if there are no gains from trade, then the price associated with an inactive centralized market is zero irrespective of the noise. Thus, the non-essentiality-of-money result is a more robust phenomenon when the centralized market acts only as a coordination device.
No Easy Road to Impredicative Definabilism
Authors: Linnebo Øystein , Roberts Sam
Published: September 2023

Bob Hale has defended a new conception of properties that is broadly Fregean in two key respects. First, like Frege, Hale insists that every property can be defined by an open formula. Second, like Frege, but unlike later definabilists, Hale seeks to justify full impredicative property comprehension. The most innovative part of his defense, we think, is a “definability constraint” that can serve as an implicit definition of the domain of properties. We make this constraint formally precise and prove that it fails to characterize the domain uniquely. Thus, we conclude, there is no easy road to impredicative definabilism.
Reliability and Validity of the Avoidance of Daily Activities Photo Scale for Patients With Shoulder Pain (ADAP Shoulder Scale)
Authors: Ansanello Walter , dos Reis Felipe José Jandre , Tozzo Marcela Camargo , Zatiti Salomão Chade Assan , Meulders Ann , Vlaeyen Johan W S , de Oliveira Anamaria Siriani
Published: September 2023

Objective

The Avoidance of Daily Activities Photo Scale for Patients With Shoulder Pain (ADAP Shoulder Scale) was developed to assess pain-related avoidance behavior during daily activities in people with shoulder pain. However, its measurement properties must be verified according to international guidelines. As such, this study investigated the following 4 measurement properties of the ADAP Shoulder Scale: reliability, measurement errors, convergent validity, and floor and ceiling effects.

Methods

The sample comprised 100 individuals with chronic shoulder pain (43 men and 57 women; mean duration of symptoms of 29.7 [SD = 89.0] months; mean age of 44.9 [SD = 15.9] years). The mean test–retest reliability range was 5 days via the intraclass correlation coefficient (ICC). Measurement errors included the standard error of measurement and the minimal detectable change. Convergent validity was analyzed by applying the Pearson correlation with the Tampa Scale for Kinesiophobia, Pain Catastrophizing Scale, and Shoulder Pain and Disability Index.

Results

The ADAP Shoulder Scale showed excellent test–retest reliability, both in all domains and in the total score [ICC(2,1) = 0.94; 95% CI = 0.92–0.96]. The standard errors of measurement for the free-movement, high-effort, and self-care domains were 8.1%, 6.0%, and 7.6%, respectively. The minimal detectable change for the total score of the ADAP Shoulder Scale was 16.0%. The total score of the ADAP Shoulder Scale was low to moderately correlated with the total scores of the Tampa Scale for Kinesiophobia (r = 0.52), Pain Catastrophizing Scale (r = 0.30), and Shoulder Pain and Disability Index (r = 0.72). No floor or ceiling effects were detected in the total score.

Conclusion

The ADAP Shoulder Scale is a reliable, valid instrument for assessing avoidance behavior in adults who have chronic shoulder pain and are not athletes.

Impact

This study provides evidence that the ADAP Shoulder Scale is appropriate for clinical and practical use in people with chronic shoulder pain.
Disability Prestige and Perceived Disability Disadvantage: Intersubjective Structure of Disability as a Social Disadvantage in the Japanese Metropolitan Area
Authors: Sakakibara Kenjiro
Published: September 2023

This paper explores disability disadvantage in Japanese society by analyzing the structure of people’s perceptions. Following in part the occupational prestige ranking, a random-sampled postal survey conducted in 2018 in the Southern Kanto District of Japan measured the extent to which respondents thought 33 different bodily conditions were an impediment to aspects of social life (e.g. work, school, and marriage) on a six-point scale. There were 248 valid cases (24.8%) out of the sample of 1,000 persons. Based on the mean scores for each bodily condition, physical and sensory conditions ranked high, psychiatric conditions ranked in the intermediate range, and disfigurements ranked low, as confirmed by multidimensional scaling using Euclidean distance. Alternatively, based on correlations of response patterns as similarity, some clusters of disability types emerged: physical/mental incapacity, mental/physical disorders, and disfigurement. These results indicate the residual social disadvantage for some disability types according to perception in Japan, while suggesting diversity among disabilities both quantitatively and qualitatively. The latter point also implies different corporal meanings attached to different aspects of body function and structure.
Long-term effects of premenopausal bilateral oophorectomy with or without hysterectomy on physical aging and chronic medical conditions
Authors: Mielke Michelle M. , Kapoor Ekta , Geske Jennifer R. , Fields Julie A. , LeBrasseur Nathan K. , Morrow Melissa M. , Winham Stacey J. , Faubion Laura L. , Castillo Anna M. , Hofrenning Ekaterina I. , Bailey Kent R. , Rocca Walter A. , Kantarci Kejal
Published: September 2023

Objective

We examined the long-term effects of premenopausal bilateral oophorectomy (PBO) with or without concurrent or preceding hysterectomy on physical and cognitive function and on odds of chronic conditions.

Methods

We enrolled 274 women with PBO with or without concurrent or preceding hysterectomy and 240 referents aged 55 years and older who were residents of Olmsted County, MN as of the PBO or index date. Chronic conditions were assessed via medical record abstraction. Cognitive diagnoses were based on neurocognitive testing. A physical function assessment included measures of strength and mobility. Multivariable regression models compared characteristics for women with PBO <46 years, PBO 46–49 years, and referent women with adjustments for age and other confounders.

Results

The clinical visits (median age, 67 years) were a median of 22 years after the PBO or index date. Of 274 women with PBO, 161 (59%) were <46 years at PBO and 113 (41%) were 46–49 years. Compared with referents, women with a history of PBO <46 years had increased odds of arthritis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.06–2.55), asthma (OR, 1.74; 95% CI, 1.03–2.93), obstructive sleep apnea (OR, 2.00; 95% CI, 1.23–3.26), and bone fractures (OR, 2.86; 95% CI, 1.17–6.98), and walked a shorter mean distance on a 6-minute walk test (b = −18.43; P = 0.034). Compared with referents, women with a history of PBO at age 46–49 years had increased odds of arthritis (OR, 1.92; 95% CI, 1.16–3.18) and obstructive sleep apnea (OR, 2.21; 95% CI, 1.33–3.66). There were no significant differences in cognitive status in women with PBO compared with referents.

Conclusions

Women with a history of PBO with or without concurrent or preceding hysterectomy, especially at age <46 years, have more chronic conditions in late mid-life compared with referents.
Primary sclerosing cholangitis and other risk factors for post-transplant lymphoproliferative disease after liver transplantation in adults
Authors: Ruijter Bastian N. , Tushuizen Maarten E. , van der Helm Danny , Hew Mitchel , Reeven Marjolein , Vossen Ann C.T.M. , Metselaar Herold J. , Alwayn Ian P.J. , Dubbeld Jeroen , Polak Wojciech G. , van Hoek Bart
Published: September 2023

Post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of liver transplantation (LT) with morbidity and mortality. The risk factors for PTLD in adults are ill-defined. This study aimed to assess the risk factors for PTLD after LT in adults. All adult LT recipients between 1986 and 2016 from 2 centers in the Netherlands were included, with follow-up until 2020. PTLD was diagnosed according to the World Health Organization (WHO) classification. Potential risk factors for PTLD were assessed using multivariate Cox regression analysis. A total of 1281 patients were included, of whom 29 (2.3%) developed PTLD. Results show that independent risk factors for PTLD after LT in adults were no Epstein-Barr virus load monitoring strategy, primary sclerosing cholangitis as an indication for LT, era (historic era linked to more intense long-term immunosuppression), and Epstein-Barr virus-seronegative recipient. No other independent risk factors were identified in this study. Of the 207 patients with primary sclerosing cholangitis as an indication for LT, 13 (6.3%) developed PTLD versus 16 out of 1074 (1.5%) patients with other underlying liver diseases (log-rank p<0.001). The yearly PTLD incidence was higher in the first year than in the later years after LT (2.4%/y vs. 0.6%/y) for primary sclerosing cholangitis, but not for other indications (0.16%/y). In Epstein-Barr virus-seronegative recipients PTLD occurred earlier after LT, while in 97% of seropositive recipients it could occur very late after LT.
A dilemma of patients: poor quality administration of tertiary care hospitals: a cross-sectional study
Authors: Mumtaz Hassan , Hafeez Muhammad H. , Bhatti Ihtisham H. , Sahar Tooba , Khan Zohaib A. , Butt Zeelaf , Akhtar Samaa , Ali Ayaz
Published: September 2023

Introduction:

The study focuses on healthcare delivery standards in Pakistan’s tertiary care hospitals. Poor accountability and a lack of financial and human resources are the main contributing factors to a hospital’s substandard performance and low patient satisfaction rates. Feedback surveillance forms are the Achilles tendon in the quality improvement of a facility, and this practice is, unfortunately, not widely practiced in the hospitals of Pakistan. Through this paper and experience, the authors hope to shed light on the need for regular feedback surveys and implementing their results to improve healthcare quality.

Settings and Design:

A prospective, observational study of seven tertiary care hospitals in Pakistan.

Materials and Methods:

The data was collected using a survey form. Each survey form was filled out by a team comprising three public health professionals who observed the hospital and its functioning without interfering with its workings. The questionnaire was developed with the help of Tools for Assessing the Operationality of District Health Systems: Health Facility Questionnaire designated in the respective facilities. The analysis was then draughted as a qualitative narrative review. Finally, the review was broken down into an assessment of the hospital’s outpatient clinic setting, inpatient department, emergency department and other departments.

Results:

The survey was conducted at seven public sector hospitals in three major cities of Pakistan. The survey focused on administrative and nonmedical parameters of healthcare facilities. Overall, the hospitals of Lahore and Islamabad lacked mass casualty apparatus and cleanliness, and staff behaviour can be improved. The hospitals in Rawalpindi have mass casualty apparatuses in place. However, they need improvement in accessibility services and hygiene and staff attitude.

Conclusions:

The survey showed that all the hospitals had good access and accessibility, and the directions were clearly marked for the visitors. The hospital staff is knowledgeable about the hospital, but their behaviour needs to be improved. Also, the quality of the cleanliness and waiting areas is fair but needs improvements. Finally, regular cheques via regular feedback and quality assessments can improve healthcare delivery.
Comparison of nebulised 3% hypertonic saline with ipratropium bromide in treatment of children with bronchiolitis: a randomized control trial
Authors: Naveed Hina , Munir Shahzad , Rafiq Kokab , Tayyab Asma , Naseer Nauman , Hussain Irshad , Halim Micheal , Mumtaz Hassan
Published: September 2023

Introduction:

Several drugs are in use for nebulization in children with acute bronchiolitis and no study has yet been conducted to compare the treatment outcome of nebulized ipratropium bromide and nebulized 3% hypertonic saline in Pakistan.

Objective:

The objective was to compare the treatment outcome of nebulized hypertonic saline and ipratropium bromide in children with acute bronchiolitis.

Setting:

Department of Pediatrics.

Study duration:

October 2019 to March 2020.

Subjects and methods:

A total of one hundred (n=100) children of either sex diagnosed with acute bronchiolitis were enrolled and randomized either to be nebulized with 3% hypertonic saline or ipratropium bromide. Outcomes were assessed in terms of respiratory rate, heart rate, and SpO2 and respiratory distress assessment instrument score at different time intervals, length of hospital stay, and need of admission.

Results:

Respiratory rate and SPO2 improved significantly at 60 min and 24 h, respiratory distress assessment instrument improved significantly at 30 min, 60 min, and 24 h after the treatment in patients who were nebulized with hypertonic saline when compared to those nebulized with ipratropium bromide. The length of hospital stay was significantly shorter (2.63 vs. 3.82 days, P=0.008) and a lesser number of patients needed hospital admission (22% vs. 44%, P=0.019) in patients who were nebulized with hypertonic saline when compared to those nebulized with ipratropium bromide.

Conclusions:

Nebulization with 3% hypertonic saline resulted in significant improvement in symptoms, a shorter duration of hospital stay, and a lesser number of hospital admissions as compared to nebulization with ipratropium bromide in children with acute bronchiolitis.
Hepatitis is still a major health concern in Pakistan: short communication
Authors: Ochani Sidhant , Ochani Khushi , Ochani Amrita , Vohra Laiba Imran , Ochani Simran , Hasibuzzaman Md. Al , Ullah Kaleem
Published: September 2023

Hepatitis is often called a ‘silent killer’ as most patients remain asymptomatic and hence remain unaware of their illness. They are either diagnosed incidentally or get symptomatic when their illness advances years after getting the infection. In Pakistan, transmission has increased due to ignorance of sterilization techniques, sharing personal items, and unsafe healthcare practices and the burden of liver cancers and transplants has risen three-fold during the past 20 years. Chronic hepatitis often goes undetected, leading to a rise in liver cancers and transplants. Pakistan bears the second-largest burden of hepatitis C globally, with a nationwide prevalence of 4.8%. From 2015 to 2019, there was a 5% increase in hepatitis C-related deaths and an 8% increase in hepatitis B-related deaths. During the last 4 years, out of the 110 million population, only 281 578 individuals were screened for hepatitis B and C, and 1 634 614 individuals were registered at various hepatitis clinics. However, only 278 308 patients were treated. Despite a national vaccination strategy, coverage falls short, and regular screening is neglected. The burden of hepatitis-related morbidity is a considerable challenge for the Pakistani government and healthcare system, being a low-income country with limited health resources and limited access to treatment. Increased awareness, education, and emphasizing preventive measures, such as hepatitis B vaccination, is crucial. Careful supervision of healthcare workers and the promotion of safe practices are essential. Pakistan can learn and implement the Egypt model to combat hepatitis effectively. This article aims to discuss barriers and challenges and provides possible recommendations.
HIV/Sexually Transmitted Infection Screening and Eligibility for HIV Preexposure Prophylaxis Among Women Incarcerated in an Urban County Jail
Authors: Desai Jui , Krakower Douglas , Harris Barry-Lewis , Culp Sophia , Nijhawan Ank E.
Published: September 2023

Background

Incarcerated women experience high rates of HIV and sexually transmitted infections (STIs); few are offered HIV preexposure prophylaxis (PrEP). We aimed to examine HIV/STI screening rates in this population and identify PrEP eligibility.

Methods

Results of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) urine and HIV/syphilis screening in cisgender women in the Dallas County Jail were compiled from January to October 2020. An electronic health record review was conducted for a subgroup in March 2020 to identify PrEP eligibility.

Results

Overall, 4398 of 13,292 women were screened for CT and 4389 of 13,292 for GC, and among them, 479 (11%) screened for HIV and 562 (13%) for syphilis. Furthermore, 462 of 4398 (11%) were positive for CT, 323 of 4389 (7%) were positive for GC, 10 of 479 (2%) had positive HIV test results, of whom 6 (1.3%) were new diagnoses and 75 (13%) had a reactive rapid plasma reagin test. In March 2020, of 541 women screened, 90 tested positive for CT or GC. Of these 90, 70 (78%) did not receive HIV or syphilis screening, including women with these risk factors: 10 (14%) were homeless, 11 (16%) reported heroin use, and 10 (14%) reported methamphetamine use. Based on the presence of an acute bacterial STI, 17% (96 of 541) were PrEP eligible.

Conclusions

Incarcerated women had high STI rates and other risk factors for HIV acquisition, although only 1 in 5 with acute STIs (11% overall) was also screened for HIV or syphilis. HIV prevention efforts should include comprehensive STI/HIV screening, linkage to treatment, and identification of PrEP candidates.
Spinning Through History: Evolution of the Concept of Vestibular Migraine
Authors: Cha Yoon-Hee
Published: September 2023

Vestibular migraine represents a growing public health problem, imposing enormous societal burdens in the form of patient suffering, loss of productivity, and direct healthcare costs. This raises the question of how we developed our ideas about vestibular migraine and how these ideas shape how we treat it.

This review walks through the history of how our conceptualization of migraine and vestibular symptoms evolved, starting with clinical observations in ancient times, inclusion under the umbrella of Meniere’s disease, and then separation from Meniere’s disease with its own identity. Tradition, clinical observations, and diagnostic criteria developed by professional societies have played prominent roles in building our current concept of vestibular migraine. A review of the ideas that have shaped our current conception of vestibular migraine may help us to see which ones have stood the test of time and which ones should continue to evolve. As in other disciplines, we study history in medicine to be inspired, warned, and sometimes, to be freed.
Micro-heterogeneity of transmission shapes the submicroscopic malaria reservoir in coastal Tanzania
Authors: Rapp Tyler , Amagai Kano , Sinai Cyrus , Basham Christopher , Loya Mwajabu , Ngasala Sifa , Said Hamza , Muller Meredith S. , Chhetri Srijana B. , Yang Guozheng , François Ruthly , Odas Melic , Mathias Derrick , Juliano Jonathan J. , Lin Feng-Chang , Ngasala Billy , Lin Jessica T.
Published: September 2023

Background

Asymptomatic malaria may be patent (visible by microscopy) and detectable by rapid malaria diagnostic tests (RDTs), or it may be submicroscopic and only detectable by polymerase chain reaction (PCR).

Methods

To characterize the submicroscopic reservoir in an area of declining malaria transmission, asymptomatic persons >5 years of age in Bagamoyo District, Tanzania, were screened using RDT, microscopy, and PCR. We investigated the size of the submicroscopic reservoir across villages, determined factors associated with submicroscopic parasitemia, and assessed the natural history of submicroscopic malaria over four weeks.

Results

Among 6,076 participants,Plasmodium falciparumprevalence by RDT, microscopy, and PCR was 9%, 9%, and 28%, respectively, with roughly two-thirds of PCR-positive individuals harboring submicroscopic infection. Adult status, female gender, dry season months, screened windows, and bednet use were associated with submicroscopic carriage. Among 15 villages encompassing 80% of participants, the proportion of submicroscopic carriers increased with decreasing village-level malaria prevalence. Over four weeks, 23% (61/266) of submicroscopic carriers became RDT-positive and were treated, with half exhibiting symptoms. This occurred more frequently in villages with higher malaria prevalence.

Conclusions

Micro-heterogeneity in transmission impacts the size of the submicroscopic reservoir and the likelihood of submicroscopic carriers developing patent malaria in coastal Tanzania.
Malaria Stratification Mapping in Thailand to Support Prevention of Re-establishment
Authors: Bisanzio Donal , Sudathip Prayuth , Kitchakarn Suravadee , Kanjanasuwan Jerdsuda , Gopinath Deyer , Pinyajeerapat Niparueradee , Sintasath David , Shah Jui A.
Published: September 2023

Thailand aims to eliminate malaria by 2026, with 46 of the country’s 77 provinces already verified as malaria free. However, these provinces remain susceptible to the re-establishment of indigenous transmission that would threaten the national goal. Thus, the country is prioritizing national and subnational prevention of re-establishment (POR) planning while considering the spatial heterogeneity of the remaining malaria caseload. To support POR efforts, a novel non-modeling method produced a malaria stratification map at the tambon (subdistrict) level, incorporating malaria case data, environmental factors, and demographic data. The stratification analysis categorized 7,425 tambons into the following four risk strata: Local Transmission (2.9%), At Risk for Transmission (3.1%), High Risk for Reintroduction (2.9%), and Low Risk for Reintroduction (91.1%). The stratification map will support the national program to target malaria interventions in remaining hotspots and mitigate the risk of transmission in malaria-free areas.
Microbe-induced plant resistance against insect pests depends on timing of inoculation, but is consistent across climatic conditions
Authors: Sanchez-Mahecha Oriana , Klink Sophia , Rothballer Michael , Sturm Sarah , Weisser Wolfgang W. , Zytynska Sharon , Heinen Robin
Published: September 2023

To cope with abiotic and biotic stressors, plants have developed mutualistic associations with beneficial soil microbes, but little is known about how (extreme) abiotic conditions impact on microbe-induce resistance to insect herbivores.

Extreme temperatures are often accompanied by extremes in plant water availability, which together reduce plant growth and change plant physiology. There are potential consequences for increasing plant susceptibility to biotic stresses, and this poses a real challenge for plant productivity.

We evaluated how the effects of beneficial soil bacteria (Acidovorax radicis) on barley plant growth and resultant resistance against aphid infestation (Sitobion avenae) were impacted by a single heatwave event across a plant water availability gradient. We also tested if timing of bacterial inoculation (before or after the heatwave) affected bacteria-plant interactions on aphids.

We found that heatwaves affected plant biomass allocation from aboveground to belowground tissues. Inoculation withA. radicisled to reduction of aphid numbers, but depended on timing of inoculation, and led to stronger resistance when inoculations occurred closer to aphid infestation. Remarkably, microbe-induced resistance against aphids was consistent across heatwave and water availability treatments.

This study provides evidence that beneficial plant-bacteria interactions may represent a potential solution for sustainable agricultural practices to enhance plant growth and response to insect pests under climate change. Future field trials should investigate the consistency of beneficial effects reported here for a better understanding of multispecies interactions in the context of global change.
Inhibition of Parkinson’s Disease-related LRRK2 by type-I and type-II kinase inhibitors: activity and structures
Authors: Murillo Marta Sanz , Suarez Amalia Villagran , Dederer Verena , Chatterjee Deep , Louro Jaime Alegrio , Knapp Stefan , Mathea Sebastian , Leschziner Andres E
Published: September 2023

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are a common cause of familial Parkinson’s Disease (PD), and a risk factor for the sporadic form. Increased kinase activity has been shown in both familial and sporadic PD patients, making LRRK2 kinase inhibitors a major focus of drug development efforts in PD. Although significant progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-EM structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type-I inhibitor MLi-2 and the broad-spectrum type-II inhibitor GZD-824. Our structures revealed LRRK2’s kinase in the active-like state, stabilized by type-I inhibitor interactions, and an inactive DYG-out type-II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structural models provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.
Untargeted Metabolomics to Expand the Chemical Space of the Marine DiatomSkeletonema marinoi
Authors: Zulfiqar Mahnoor , Stettin Daniel , Schmidt Saskia , Nikitashina Vera , Pohnert Georg , Steinbeck Christoph , Peters Kristian , Sorokina Maria
Published: September 2023

Diatoms (Bacillariophyceae) are aquatic photosynthetic microalgae with an ecological role as primary producers in the aquatic food web. They account substantially for global carbon, nitrogen, and silicon cycling. Elucidating the chemical space of diatoms is crucial to understanding their physiology and ecology. To expand the known chemical space of a cosmopolitan marine diatom,Skeletonema marinoi, we performed High-Resolution Liquid Chromatography-Tandem Mass Spectrometry (LC-MS2) for untargeted metabolomics data acquisition. The spectral data from LC-MS2was used as input for the Metabolome Annotation Workflow (MAW) to obtain putative annotations for all measured features. A suspect list of metabolites previously identified in theSkeletonemaspp. was generated to verify the results. These known metabolites were then added to the putative candidate list from LC-MS2data to represent an expanded catalogue of 1970 metabolites estimated to be produced byS. marinoi. The most prevalent chemical superclasses, based on the ChemONT ontology in this expanded dataset, were “Organic acids and derivatives”, “Organoheterocyclic compounds”, “Lipids and lipid-like molecules”, and “Organic oxygen compounds”. The metabolic profile from this study can aid the bioprospecting of marine microalgae for medicine, biofuel production, agriculture, and environmental conservation. The proposed analysis can be applicable for assessing the chemical space of other microalgae, which can also provide molecular insights into the interaction between marine organisms and their role in the functioning of ecosystems.

Importance

Diatoms are abundant marine phytoplankton members and have great ecological importance and biochemical potential. The cosmopolitan diatomSkeletonema marinoihas become an ecological and environmental research model organism. In this study, we used untargeted metabolomics to acquire a general metabolic profile ofS. marinoito assess its chemical diversity and expand the known metabolites produced by this diatom.S. marinoiproduces a chemically diverse set of secondary metabolites with potential therapeutic properties, such as anti-cancer, antioxidant, and anti-inflammatory. Such metabolites are highly significant due to their potential role in drug discovery and bioeconomy. Lipids fromS. marinoialso have potential in the biofuel industry. Furthermore, the environmental fluctuations in the water bodies directly affect the production of different secondary metabolites from diatoms, which can be key indicators of climate change.
“Invisible Killer”: Seasonal Allergies and Accidents
Authors: Akesaka Mika , Shigeoka Hitoshi
Published: September 2023

Although at least 400 million people suffer from seasonal allergies worldwide, the adverse effects of pollen on “non-health” outcomes, such as cognition and productivity, are relatively understudied. Using ambulance archives from Japan, we demonstrate that high pollen days are associated with increased accidents and injuries— one of the most extreme consequences of cognitive impairment. We find some evidence of avoidance behavior in buying allergy products but limited evidence in curtailing outdoor activity, implying that the cognitive risk of pollen exposure is discounted. Our results call for governmental efforts to raise public awareness of the risks and promote widespread behavioral change.
Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification
Authors: Ryu Jayoung , Barkal Sam , Yu Tian , Jankowiak Martin , Zhou Yunzhuo , Francoeur Matthew , Phan Quang Vinh , Li Zhijian , Tognon Manuel , Brown Lara , Love Michael I. , Lettre Guillaume , Ascher David B. , Cassa Christopher A. , Sherwood Richard I. , Pinello Luca
Published: September 2023

CRISPR base editing screens are powerful tools for studying disease-associated variants at scale. However, the efficiency and precision of base editing perturbations vary, confounding the assessment of variant-induced phenotypic effects. Here, we provide an integrated pipeline that improves the estimation of variant impact in base editing screens. We perform high-throughput ABE8e-SpRY base editing screens with an integrated reporter construct to measure the editing efficiency and outcomes of each gRNA alongside their phenotypic consequences. We introduce BEAN, a Bayesian network that accounts for per-guide editing outcomes and target site chromatin accessibility to estimate variant impacts. We show this pipeline attains superior performance compared to existing tools in variant classification and effect size quantification. We use BEAN to pinpoint common variants that alter LDL uptake, implicating novel genes. Additionally, through saturation base editing ofLDLR, we enable accurate quantitative prediction of the effects of missense variants on LDL-C levels, which aligns with measurements in UK Biobank individuals, and identify structural mechanisms underlying variant pathogenicity. This work provides a widely applicable approach to improve the power of base editor screens for disease-associated variant characterization.
Ventilation during COVID-19 in a school for students with intellectual and developmental disabilities (IDD)
Authors: Zand Martin S. , Spallina Samantha , Ross Alexis , Zandi Karen , Pawlowski Anne , Seplaki Christopher L. , Herington Jonathan , Corbett Anthony M. , Kaukeinen Kimberly , Holden-Wiltse Jeanne , Freedman Edward G. , Alcantara Lisette , Li Dongmei , Cameron Andrew , Beaumont Nicole , Dozier Ann , Dewhurst Stephen , Foxe John J.
Published: September 2023

Background

This study examined the correlation of classroom ventilation (air exchanges per hour (ACH)) and exposure to CO2≥1,000 ppm with the incidence of SARS-CoV-2 over a 20-month period in a specialized school for students with intellectual and developmental disabilities (IDD). These students were at a higher risk of respiratory infection from SARS-CoV-2 due to challenges in tolerating mitigation measures (e.g. masking). One in-school measure proposed to help mitigate the risk of SARS-CoV-2 infection in schools is increased ventilation.

Methods

We established a community-engaged research partnership between the University of Rochester and the Mary Cariola Center school for students with IDD. Ambient CO2levels were measured in 100 school rooms, and air changes per hour (ACH) were calculated. The number of SARS-CoV-2 cases for each room was collected over 20 months.

Results

97% of rooms had an estimated ACH≤4.0, with 7% having CO2levels≥2,000 ppm for up to 3 hours per school day. A statistically significant correlation was found between the time that a room had CO2levels ≥1,000 ppm and SARS-CoV-2 PCR tests normalized to room occupancy, accounting for 43% of the variance. No statistically significant correlation was found for room ACH and per-room SARS-CoV-2 cases. Rooms with ventilation systems using MERV-13 filters had lower SARS-CoV-2-positive PCR counts. These findings led to ongoing efforts to upgrade the ventilation systems in this community-engaged research project.

Conclusions

There was a statistically significant correlation between the total time of room CO2concentrations ≥1,000 and SARS-CoV-2 cases in an IDD school. Merv-13 filters appear to decrease the incidence of SARS-CoV-2 infection. This research partnership identified areas for improving in-school ventilation.
DIMR Score: A Tool for Determining the Destination of LVO Patients After Thrombolysis
Authors: Rao Rahul , Ali Aizaz , Zoghi Zeinab , Shawver Julie , Burgess Richard , Zaidi Syed , Jumaa Mouhammad
Published: September 2023

Background

Stroke patients with large vessel occlusion (LVO) benefit from thrombolysis (tPA) and mechanical thrombectomy (MT). We aim to characterize triaging patterns in these patients, specifically those who go to perfusion-based imaging first or direct to angio in the drip-and-ship model. Furthermore, we propose that select patients may benefit from CTP prior to MT.

Methods

A total of 270 patients with acute ischemic stroke secondary to LVO/MeVO were retrospectively evaluated from January 2018 to June 2022. These patients received intravenous tPA from the outside hospital and were transferred for the intention of MT. We compared baseline characteristics between those who received CTP upon arrival and those who went either directly to the angiography suite (DTA) along with logistic regression and functional outcomes.

Results

Predictors of CTP utilization over DTA was the presence of an M3 occlusion (11.3% vs. 1.7%, p=0.005) and PCA occlusion (12.9% vs. 3.4%, p=0.015). The DTA approach was higher in M1 MCA occlusions (43.2% vs. 27.4%, p=0.038) and basilar occlusions (7.6% vs. 0, p=0.026). DTA patients had a higher NIHSS at the spoke (median NIHSS 15 [9-21] vs. 9 [4.75-14], p<0.001) and the hub (14 [7-20] vs. 7 [3-15.75], p<0.001). There was no significant difference between the DTA and CTP groups in regards to mRS at 90 days (39% vs. 48.4%, p=0.101).

Conclusion

In the drip-and-ship model, NIHSS and location of an occlusion on initial CTA guide CTP utilization in LVO/ MeVO patients. Long term functional outcomes are not significantly affected by arrival at CTP over DTA. Patients whose transfer is delayed, improve after thrombolysis, present with a MeVO, or are limited by resources at the CSC may benefit from transfer to CT over a DTA approach. We propose this DIMR score may help guide triaging of patients who have an intracranial occlusion and receive thrombolysis.
Methylotrophic methanogenesis in the Archaeoglobi revealed by cultivation ofCa.Methanoglobus hypatiae from a Yellowstone hot spring
Authors: Lynes Mackenzie M. , Jay Zackary J. , Kohtz Anthony J. , Hatzenpichler Roland
Published: September 2023

Over the past decade, environmental metagenomics and PCR-based marker gene surveys have revealed that several lineages beyond just a few well-established groups within the Euryarchaeota superphylum harbor the genetic potential for methanogenesis. One of these groups are the Archaeoglobi, a class of thermophilic euryarchaeotes that have long been considered to live non-methanogenic lifestyles. Here, we enrichedCandidatusMethanoglobus hypatiae, a methanogen affiliated with the family Archaeoglobaceae, from a hot spring in Yellowstone National Park. The enrichment is sediment-free, grows at 64-70 °C and a pH of 7.8, and produces methane from mono-, di-, and tri-methylamine.Ca.M. hypatiae is represented by a 1.62 Mb metagenome-assembled genome with an estimated completeness of 100% and accounts for up to 67% of cells in the culture according to fluorescencein situhybridization. Via genome-resolved metatranscriptomics and stable isotope tracing, we demonstrate thatCa.M. hypatiae expresses methylotrophic methanogenesis and energy-conserving pathways for reducing monomethylamine to methane. The detection of Archaeoglobi populations related toCa.M. hypatiae in 36 geochemically diverse geothermal sites within Yellowstone National Park, as revealed through the examination of previously published gene amplicon datasets, implies a previously underestimated contribution to anaerobic carbon cycling in extreme ecosystems.
A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match
Authors: Verheyden Nikita A. , Klostermann Melina , Brüggemann Mirko , Steede Hanna M. , Scholz Anica , Amr Shady , Lichtenthaeler Chiara , Münch Christian , Schmid Tobias , Zarnack Kathi , Krueger Andreas
Published: September 2023

MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3’ untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.

Key Points

• Deep profiling identifies novel targets of miR-181 associated with global gene regulation.

• miR-181 MREs in repeat elements in the coding sequence act through translational inhibition.

• High-resolution analysis reveals an alternative seed match in functional MREs.
Encoding the Space of Protein-protein Binding Interfaces by Artificial Intelligence
Authors: Su Zhaoqian , Dhusia Kalyani , Wu Yinghao
Published: September 2023

The physical interactions between proteins are largely determined by the structural properties at their binding interfaces. It was found that the binding interfaces in distinctive protein complexes are highly similar. The structural properties underlying different binding interfaces could be further captured by artificial intelligence. In order to test this hypothesis, we broke protein-protein binding interfaces into pairs of interacting fragments. We employed a generative model to encode these interface fragment pairs in a low-dimensional latent space. After training, new conformations of interface fragment pairs were generated. We found that, by only using a small number of interface fragment pairs that were generated by artificial intelligence, we were able to guide the assembly of protein complexes into their native conformations. These results demonstrate that the conformational space of fragment pairs at protein-protein binding interfaces is highly degenerate. Our study illustrates how artificial intelligence can be used to understand and characterize protein-protein binding interfaces. The method will be potentially useful to search for the conformation of unknown protein-protein interactions. This result demonstrated that the structural space of protein-protein interactions is highly degenerate under the representation of interface fragment pairs. Features in this degenerate space can be well characterized by artificial intelligence. In summary, our machine learning method will be potentially useful to search for and predict the conformations of unknown protein-protein interactions.
Targeting YAP mechanosignaling to ameliorate stiffness-induced Schlemm’s canal cell pathobiology
Authors: Li Haiyan , Kuhn Megan , Kelly Ruth A. , Singh Ayushi , Palanivel Kavipriya Kovai , Salama Izzy , De Ieso Michael L. , Stamer W. Daniel , Ganapathy Preethi S. , Herberg Samuel
Published: September 2023

Pathologic alterations in the biomechanical properties of the Schlemm’s canal (SC) inner wall endothelium and its immediate vicinity are strongly associated with ocular hypertension in glaucoma due to decreased outflow facility. Specifically, the underlying trabecular meshwork is substantially stiffer in glaucomatous eyes compared to that from normal eyes. This raises the possibility of a critical involvement of mechanotransduction processes in driving SC cell dysfunction. Yes-associated protein (YAP) has emerged as a key contributor to glaucoma pathogenesis. However, the molecular underpinnings of SC cell YAP mechanosignaling in response to glaucomatous extracellular matrix (ECM) stiffening are not well understood. Using a novel biopolymer hydrogel that facilitates dynamic and reversible stiffness tuning, we investigated how ECM stiffening modulates YAP activity in primary human SC cells, and whether disruption of YAP mechanosignaling attenuates SC cell pathobiology and increasesex vivooutflow facility. We demonstrated that ECM stiffening drives pathologic YAP activation and cytoskeletal reorganization in SC cells, which was fully reversible by matrix softening in a distinct time-dependent manner. Furthermore, we showed that pharmacologic or genetic disruption of YAP mechanosignaling abrogates stiffness-induced SC cell dysfunction involving altered cytoskeletal and ECM remodeling. Lastly, we found that perfusion of the clinically-used, small molecule YAP inhibitor verteporfin (without light activation) increasesex vivooutflow facility in normal mouse eyes. Collectively, our data provide new evidence for a pathologic role of aberrant YAP mechanosignaling in SC cell dysfunction and suggest that YAP inhibition has therapeutic value for treating ocular hypertension in glaucoma.