bluuebunny/crossref_metadata_2025 huggingface dataset:
A chart review on surgical myocardial debridging in symptomatic patients: a safe procedure with good long-term clinical outcome and coronary computed tomographic angiography results
Authors: Charaf Zohra , Tanaka Kaoru , Wellens Francis , Nijs Jan , Van Loo Ines , Argacha Jean-Francois , La Meir Mark
Published: January 2023

OBJECTIVES

Myocardial bridging is mostly diagnosed as an incidental imaging finding but can result in severe vessel compression and significant clinical adverse complications. Since there is still an ongoing debate when to propose surgical unroofing, we studied a group of patients where this was performed as an isolated procedure.

METHODS

In 16 patients (38.9 ± 15.7 years, 75% men) who had surgical unroofing for symptomatic isolated myocardial bridges of the left anterior descending artery, we retrospectively analysed symptomatology, medication, imaging modalities used, operative techniques, complications and long-term outcome. Computed tomographic fractional flow reserve was calculated to understand its potential value for decision-making.

RESULTS

Most procedures were performed on-pump (75%, mean cardiopulmonary bypass 56.5 ± 27.9 min, mean aortic cross-clamping 36.4 ± 19.7 min). Three patients needed a left internal mammary artery bypass since the artery dived inside the ventricle. There were no major complications or deaths. The mean follow-up was 5.5 years. Although there was a dramatic improvement in symptoms, still 31% experienced atypical chest pain at various moments during follow-up. Postoperative radiological control was performed in 88%, showing no residual compression or recurrent myocardial bridge and patent bypass if performed. All postoperative computed tomographic flow calculations (7) showed a normalization of coronary flow.

CONCLUSIONS

Surgical unroofing for symptomatic isolated myocardial bridging is a safe procedure. Patient selection remains difficult but introducing standard coronary computed tomographic angiography with flow calculations could be helpful in preoperative decision-making and during follow-up.
Climate Change, Energy Transition, and Constitutional Identity
Authors: Maloy J S
Published: January 2023

Through its potential to contribute to mass suffering, economic disruption, and social unrest, climate change poses a security threat to the constitutional identities of states (as democratic, autocratic, or hybrid regimes). This paper proposes a conceptual framework of mediated causality for climatic impacts on constitutional identity and engages in novel theory-building for one mediating vector of change: the post-fossil energy transition. Theories of the “oil curse” and of “carbon democracy” are compared and critiqued for their contributions to understanding the potential impacts of decarbonized energy systems on democracy. Two counterintuitive conclusions emerge. First, transitioning away from petroleum may not result in increased democratization, as the oil curse implies. Second, post-fossil energy systems are unlikely to become structurally decentralized, as advocates of “energy democracy” suppose, and may even need to remain centralized in order for popular mobilization around energy to help maintain or reinvigorate democratic rights.
Not so weak PICO: leveraging weak supervision for participants, interventions, and outcomes recognition for systematic review automation
Authors: Dhrangadhariya Anjani , Müller Henning
Published: January 2023

Objective

The aim of this study was to test the feasibility of PICO (participants, interventions, comparators, outcomes) entity extraction using weak supervision and natural language processing.

Methodology

We re-purpose more than 127 medical and nonmedical ontologies and expert-generated rules to obtain multiple noisy labels for PICO entities in the evidence-based medicine (EBM)-PICO corpus. These noisy labels are aggregated using simple majority voting and generative modeling to get consensus labels. The resulting probabilistic labels are used as weak signals to train a weakly supervised (WS) discriminative model and observe performance changes. We explore mistakes in the EBM-PICO that could have led to inaccurate evaluation of previous automation methods.

Results

In total, 4081 randomized clinical trials were weakly labeled to train the WS models and compared against full supervision. The models were separately trained for PICO entities and evaluated on the EBM-PICO test set. A WS approach combining ontologies and expert-generated rules outperformed full supervision for the participant entity by 1.71% macro-F1. Error analysis on the EBM-PICO subset revealed 18–23% erroneous token classifications.

Discussion

Automatic PICO entity extraction accelerates the writing of clinical systematic reviews that commonly use PICO information to filter health evidence. However, PICO extends to more entities—PICOS (S—study type and design), PICOC (C—context), and PICOT (T—timeframe) for which labelled datasets are unavailable. In such cases, the ability to use weak supervision overcomes the expensive annotation bottleneck.

Conclusions

We show the feasibility of WS PICO entity extraction using freely available ontologies and heuristics without manually annotated data. Weak supervision has encouraging performance compared to full supervision but requires careful design to outperform it.
Forages and Pastures Symposium: revisiting mechanisms, methods, and models for altering forage cell wall utilization for ruminants
Authors: Tedeschi Luis O , Adams Jordan M , Vieira Ricardo A M
Published: January 2023

Several ruminant animals rely almost exclusively on the complex polysaccharide matrix from the plant cell wall (CW) as their primary energy source via volatile fatty acids produced through ruminal and some hindgut fermentation processes. The CW contains different types and proportions of polysaccharides, proteins, phenolic compounds, and minerals in their macromolecular structure that influence the rate and extent of fiber digestion and selective retention of particulate matter due to its physical characteristics (buoyancy and comminuting) in the reticulorumen. The biosynthetic formation of the CW dictates possible manipulation mechanisms (targeted plant and microbes selection) and processing methods (physical, chemical, microbial, and enzymatic treatments and the use of genetically engineered bacteria) to increase its digestibility, leading to better utilization of the CW by the ruminant animal and hopefully lower the contribution of ruminants’ greenhouse gas emissions. Early studies on lignin biosynthesis have led to more advanced studies focusing on replacing traditional monolignols with homopolymers that are easier to deconstruct or degrade. Concurrently, laboratory methods must be developed, evaluated, and modified to accurately reflect the digestibility and nutritive value of CW brought about by modern manipulation mechanisms or processing methods. However, the laboratory methods must also be reliable, precise, feasible, trivial, easy to implement, and cost-effective, but at the same time environmentally friendly and aware. For instance, although the acid detergent lignin has been demonstrated to behave uniformly as a nutritional entity, its chemical determination and association with carbohydrates still lack consensus. Spectroscopy (near-infrared and Raman) and in vitro gas production techniques have been adopted to assess plant chemical composition and nutritive value, but an incomplete understanding of the impacts caused by disrupting the CW for sample processing still exists. Different variations of multicompartmental and time- and age-dependent mathematical models have been proposed to determine the ruminal rates of degradation and passage of fiber. However, low-quality and incomplete data due to inconsistent marker results used to determine passage rates and transit time of fiber in the gastrointestinal tract have hindered advancements and adoptions of the next generation of computer models to understand ruminal fiber degradation.
Hot white dwarfs and pre-white dwarfs discovered with SALT
Authors: Jeffery C S , Werner K , Kilkenny D , Miszalski B , Monageng I , Snowdon E J
Published: January 2023

The Southern African Large Telescope survey of helium-rich hot subdwarfs aims to explore evolutionary pathways among groups of highly evolved stars. The selection criteria mean that several hot white dwarfs and related objects have also been included. This paper reports the discovery and analysis of eight new very hot white dwarf and pre-white dwarf stars with effective temperatures exceeding 100 000 K. They include two PG1159 stars, one DO white dwarf, three O(He), and two O(H) stars. One of the O(H) stars is the central star of a newly discovered planetary nebula, and the other is the hottest ‘naked’ O(H) star. Both of the PG1159 stars are GW Vir variables, one being the hottest GW Vir star measured and a crucial test for pulsation stability models. The DO white dwarf is also the hottest in its class.
Identification and characterization of RNA binding sites for (p)ppGpp using RNA-DRaCALA
Authors: Jagodnik Jonathan , Tjaden Brian , Ross Wilma , Gourse Richard L
Published: January 2023

Ligand-binding RNAs (RNA aptamers) are widespread in the three domains of life, serving as sensors of metabolites and other small molecules. When aptamers are embedded within RNA transcripts as components of riboswitches, they can regulate gene expression upon binding their ligands. Previous methods for biochemical validation of computationally predicted aptamers are not well-suited for rapid screening of large numbers of RNA aptamers. Therefore, we utilized DRaCALA (Differential Radial Capillary Action of Ligand Assay), a technique designed originally to study protein-ligand interactions, to examine RNA-ligand binding, permitting rapid screening of dozens of RNA aptamer candidates concurrently. Using this method, which we call RNA-DRaCALA, we screened 30 ykkC family subtype 2a RNA aptamers that were computationally predicted to bind (p)ppGpp. Most of the aptamers bound both ppGpp and pppGpp, but some strongly favored only ppGpp or pppGpp, and some bound neither. Expansion of the number of biochemically verified sites allowed construction of more accurate secondary structure models and prediction of key features in the aptamers that distinguish a ppGpp from a pppGpp binding site. To demonstrate that the method works with other ligands, we also used RNA DRaCALA to analyze aptamer binding by thiamine pyrophosphate.
Poison cassette exon splicing ofSRSF6regulates nuclear speckle dispersal and the response to hypoxia
Authors: de Oliveira Freitas Machado Camila , Schafranek Michal , Brüggemann Mirko , Hernández Cañás María Clara , Keller Mario , Di Liddo Antonella , Brezski Andre , Blümel Nicole , Arnold Benjamin , Bremm Anja , Wittig Ilka , Jaé Nicolas , McNicoll François , Dimmeler Stefanie , Zarnack Kathi , Müller-McNicoll Michaela
Published: January 2023

Hypoxia induces massive changes in alternative splicing (AS) to adapt cells to the lack of oxygen. Here, we identify the splicing factor SRSF6 as a key factor in the AS response to hypoxia. The SRSF6 level is strongly reduced in acute hypoxia, which serves a dual purpose: it allows for exon skipping and triggers the dispersal of nuclear speckles. Our data suggest that cells use dispersal of nuclear speckles to reprogram their gene expression during hypoxic adaptation and that SRSF6 plays an important role in cohesion of nuclear speckles. Down-regulation of SRSF6 is achieved through inclusion of a poison cassette exon (PCE) promoted by SRSF4. Removing the PCE 3′ splice site using CRISPR/Cas9 abolishes SRSF6 reduction in hypoxia. Aberrantly high SRSF6 levels in hypoxia attenuate hypoxia-mediated AS and impair dispersal of nuclear speckles. As a consequence, proliferation and genomic instability are increased, while the stress response is suppressed. The SRSF4–PCE–SRSF6 hypoxia axis is active in different cancer types, and high SRSF6 expression in hypoxic tumors correlates with a poor prognosis. We propose that the ultra-conserved PCE of SRSF6 acts as a tumor suppressor and that its inclusion in hypoxia is crucial to reduce SRSF6 levels. This may prevent tumor cells from entering the metastatic route of hypoxia adaptation.
DPC29promotes post-initiation mitochondrial translation inSaccharomyces cerevisiae
Authors: Hubble Kyle A , Henry Michael F
Published: January 2023

Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans—TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We found this 29 kDa protein to be a general mitochondrial translation factor, Dpc29, rather than a COX1-specific translational activator. Its activity was necessary for the optimal expression of OXPHOS mtDNA reporters, and mutations within the mitoribosomal large subunit protein gene MRP7 produced a global reduction of mitochondrial translation in dpc29Δ cells, indicative of a general mitochondrial translation factor. Northern-based mitoribosome profiling of dpc29Δ cells showed higher footprint frequencies at the 3' ends of mRNAs, suggesting a role in translation post-initiation. Additionally, human TACO1 expressed at native levels rescued defects in dpc29Δ yeast strains, suggesting that the two proteins perform highly conserved functions.
Cryo-EM structure of the fully assembled Elongator complex
Authors: Jaciuk Marcin , Scherf David , Kaszuba Karol , Gaik Monika , Rau Alexander , Kościelniak Anna , Krutyhołowa Rościsław , Rawski Michał , Indyka Paulina , Graziadei Andrea , Chramiec-Głąbik Andrzej , Biela Anna , Dobosz Dominika , Lin Ting-Yu , Abbassi Nour-el-Hana , Hammermeister Alexander , Rappsilber Juri , Kosinski Jan , Schaffrath Raffael , Glatt Sebastian
Published: January 2023

Transfer RNA (tRNA) molecules are essential to decode messenger RNA codons during protein synthesis. All known tRNAs are heavily modified at multiple positions through post-transcriptional addition of chemical groups. Modifications in the tRNA anticodons are directly influencing ribosome decoding and dynamics during translation elongation and are crucial for maintaining proteome integrity. In eukaryotes, wobble uridines are modified by Elongator, a large and highly conserved macromolecular complex. Elongator consists of two subcomplexes, namely Elp123 containing the enzymatically active Elp3 subunit and the associated Elp456 hetero-hexamer. The structure of the fully assembled complex and the function of the Elp456 subcomplex have remained elusive. Here, we show the cryo-electron microscopy structure of yeast Elongator at an overall resolution of 4.3 Å. We validate the obtained structure by complementary mutational analyses in vitro and in vivo. In addition, we determined various structures of the murine Elongator complex, including the fully assembled mouse Elongator complex at 5.9 Å resolution. Our results confirm the structural conservation of Elongator and its intermediates among eukaryotes. Furthermore, we complement our analyses with the biochemical characterization of the assembled human Elongator. Our results provide the molecular basis for the assembly of Elongator and its tRNA modification activity in eukaryotes.
Detection of unintended on-target effects in CRISPR genome editing by DNA donors carrying diagnostic substitutions
Authors: Lackner Martin , Helmbrecht Nelly , Pääbo Svante , Riesenberg Stephan
Published: January 2023

CRISPR nucleases can introduce double-stranded DNA breaks in genomes at positions specified by guide RNAs. When repaired by the cell, this may result in the introduction of insertions and deletions or nucleotide substitutions provided by exogenous DNA donors. However, cellular repair can also result in unintended on-target effects, primarily larger deletions and loss of heterozygosity due to gene conversion. Here we present a strategy that allows easy and reliable detection of unintended on-target effects as well as the generation of control cells that carry wild-type alleles but have demonstratively undergone genome editing at the target site. Our ‘sequence-ascertained favorable editing’ (SAFE) donor approach relies on the use of DNA donor mixtures containing the desired nucleotide substitutions or the wild-type alleles together with combinations of additional ‘diagnostic’ substitutions unlikely to have any effects. Sequencing of the target sites then results in that two different sequences are seen when both chromosomes are edited with ‘SAFE’ donors containing different sets of substitutions, while a single sequence indicates unintended effects such as deletions or gene conversion. We analyzed more than 850 human embryonic stem cell clones edited with ‘SAFE’ donors and detect all copy number changes and almost all clones with gene conversion.
Structural insights into translation regulation by the THF-II riboswitch
Authors: Xu Lilei , Xiao Yu , Zhang Jie , Fang Xianyang
Published: January 2023

In bacteria, expression of folate-related genes is controlled by the tetrahydrofolate (THF) riboswitch in response to specific binding of THF and its derivatives. Recently, a second class of THF riboswitches, named THF-II, was identified in Gram-negative bacteria, which exhibit distinct architecture from the previously characterized THF-I riboswitches found in Gram-positive bacteria. Here, we present the crystal structures of the ligand-bound THF-II riboswitch from Mesorhizobium loti. These structures exhibit a long rod-like fold stabilized by continuous base pair and base triplet stacking across two helices of P1 and P2 and their interconnecting ligand-bound binding pocket. The pterin moiety of the ligand docks into the binding pocket by forming hydrogen bonds with two highly conserved pyrimidines in J12 and J21, which resembles the hydrogen-bonding pattern at the ligand-binding site FAPK in the THF-I riboswitch. Using small-angle X-ray scattering and isothermal titration calorimetry, we further characterized the riboswitch in solution and reveal that Mg2+ is essential for pre-organization of the binding pocket for efficient ligand binding. RNase H cleavage assay indicates that ligand binding reduces accessibility of the ribosome binding site in the right arm of P1, thus down-regulating the expression of downstream genes. Together, these results provide mechanistic insights into translation regulation by the THF-II riboswitch.
No Sufficient Evidence for an Immediate Hypoalgesic Effect of Spinal Manual Therapy on Pressure Pain Thresholds in Asymptomatic and Chronic Pain Populations: A Systematic Review and Meta-Analysis
Authors: Jung Andres , Adamczyk Waclaw M , Ahmed Abdallah , van der Schalk Lea , Poesl Matthias , Luedtke Kerstin , Szikszay Tibor M
Published: January 2023

Objective

Spinal manual therapy (SMT) is often used to treat patients with spinal disorders; however, the underlying mechanisms of SMT are not fully understood. This systematic review and meta-analysis investigates the effect of SMT compared with sham treatment or no intervention on local or remote (segmental or non-segmental) pressure pain thresholds (PPTs) in patients with chronic musculoskeletal conditions and people who are pain free.

Methods

A systematic search was conducted in the PubMed, Cochrane Library, Web of Science, and CINAHL databases. Randomized controlled trials investigating the effect of SMT on PPTs in patients with chronic musculoskeletal conditions and in people who were pain free were included. Quality assessment and evidence synthesis were performed according to Cochrane Handbook recommendations. A meta-analysis was performed using standardized mean difference and 95% CIs.

Results

Twenty-two reports were included in the present review. There were no significant results for an immediate effect of SMT on local (low certainty of evidence), remote (segmental) (low certainty of evidence), and remote (non-segmental) (low certainty of evidence) PPTs in patients with chronic pain as well as on local (moderate certainty of evidence) and remote (segmental) (low certainty of evidence) PPTs in people who were pain free. A small but significant effect (standardized mean difference = 0.26; 95% CI = 0.01 to 0.51; low certainty of evidence) was observed on remote (non-segmental) PPTs in people who were pain free, which was not considered a meaningful effect size.

Conclusion

No immediate, consistent, or meaningful hypoalgetic effect of SMT was shown on PPTs on various body areas. Involvement of spinal or supraspinal underlying mechanisms were, therefore, not confirmed via PPTs but should still be investigated using methods designed to assess central nervous pain processing.

Impact

No consistent and meaningful hypoalgesic effects of spinal manual therapy were demonstrated on PPTs in participants who were pain free and in patients with chronic musculoskeletal disorders.
The joint effects of nanoplastics and TBBPA on neurodevelopmental toxicity inCaenorhabditis elegans
Authors: Zhao Kunming , Zhang Ying , Liu Mingyuan , Huang Yuecheng , Wang Siyan , An Jing , Wang Yan , Shang Yu
Published: January 2023

Both of nanoplastics (NPs) and Tetrabromobisphenol A (TBBPA) are organic pollutants widely detected in the environment and organisms. The large specific surface area of NPs makes them ideal vectors for carrying various toxicants, such as organic pollutants, metals, or other nanomaterials, posing potential threats to human health. This study used Caenorhabditis elegans (C. elegans) to investigate the neurodevelopmental toxicity induced by combined exposure of TBBPA and polystyrene NPs. Our results showed that combined exposure caused synergistic inhibitory effects on the survival rate, body length/width, and locomotor ability. Furthermore, the overproduction of reactive oxygen species (ROS), lipofuscin accumulation, and dopaminergic neuronal loss suggested that oxidative stress was involved in induction of neurodevelopmental toxicity in C. elegans. The expressions of Parkinson’s disease related gene (pink-1) and Alzheimer’s disease related gene (hop-1) were significantly increased after combined exposure of TBBPA and polystyrene NPs. Knock out of pink-1 and hop-1 genes alleviated the adverse effects such as growth retardation, locomotion deficits, dopaminergic loss, and oxidative stress induction, indicating that pink-1 and hop-1 genes play an important role in neurodevelopmental toxicity induced by TBBPA and polystyrene NPs. In conclusion, TBBPA and polystyrene NPs had synergistic effect on oxidative stress induction and neurodevelopmental toxicity in C. elegans, which was mediated through increased expressions of pink-1 and hop-1.
Health Literacy of Surrogates and Communication Issues in Palliative Care Conversations in Critical Care
Authors: Baltazar Alberto O. , Popejoy Lori
Published: January 2023

Worldwide, 56.8 million persons are estimated to require palliative care. Critically ill patients benefit from palliative care by improving their quality of life through symptom management. Resistance to palliative care exists from surrogate decision-makers because of low health literacy and communication issues with providers. This research reviewed the literature to identify how health literacy and health care communication influenced palliative care conversations with decision-making surrogates and health outcomes of critically ill patients. The review included articles between 2011 and 2022 using the termscommunication,health literacy,palliative care,critical care,intensive care,ICU,surrogate decision maker,family, andcaregiverin PubMed, CINAHL, and Google Scholar. Fourteen articles were included. Quality was assessed through Joanna Briggs Institute appraisal tools. Health literacy of surrogates was not found to be significant for patient outcomes. However, there were significant differences between clinician and surrogate communication influenced by surrogates' previous health care experiences. Early communication about prognosis was important for surrogates. Structured communication approaches were preferred by surrogates. Limitations of the review included primarily White participants, small variability of research sites, and a few number of articles. Future research needs to study the effects of surrogate health literacy of critically ill patients on willingness to accept palliative care.
Case Report: Kingella kingae causing prosthetic joint infection in an adult
Authors: Wensley Katherine , McClelland Damian , Grocott Natalie , Manoharan Gopikanthan , Desai Seema
Published: January 2023

Introduction

Kingella kingae (K. kingae) is a gram-negative microorganism that is rare in the adult population, apart from occasional reports in those who are immunocompromised. Although widely reported to affect prosthetic heart valves, to our knowledge, there have been no previously reported cases of K. kingae infecting prosthetic joints.
Case:
A 61 year-old patient with a history of rheumatoid arthritis since 1986, presented to the rheumatology clinic with insidious onset of pain and swelling in her right shoulder, which had progressed to a discharging sinus. The patient had undergone a total shoulder replacement 11 years previously and had not had any post-operative complications or previous infections in the shoulder.  The patient subsequently underwent a two stage revision procedure. In the first stage, the implant was removed, the sinus excised and an extensive debridement and washout was performed. A temporary antibiotic loaded spacer was implanted. Tissue samples and culture swabs were sent for microbiological culture and grew K. Kingae at 5 days post-operatively. The patient was commenced on intravenous ceftriaxone for 14 days, followed by a further 28 days of oral ciprofloxacin. A second stage was undertaken at 10 months following the first stage and the patient made a good recovery with satisfactory return of function.

Conclusion

The authors suggest that clinicians should be attuned to K. kingae as a potential cause of periprosthetic joint infection, particularly in patients with immune compromise. Adherence to specific culture and isolation techniques can facilitate diagnosis of this fastidious organism, ensuring prompt and appropriate treatment.
A comparison of culture methods and polymerase chain reaction in detecting Clostridioides difficile from hospital surfaces
Authors: Grainger Rachel J. , Kearney Aoife , Humphreys Hilary , Stevens Niall T.
Published: January 2023

Introduction. Environmental surveillance for

Clostridioides difficile

is challenging. There are no internationally agreed recommendations on which method should be used when environmental surveillance is undertaken.

Aim. To compare the detection of

C. difficile

by RT-PCR to culture-based methods and to determine which is more sensitive and specific in the clinical environment.

Methods. Forty-four near-patient areas of

C. difficile

-positive patients were sampled using contact plates and moistened flocked swabs.

Results. Detection using moistened flocked swabs followed by RT-PCR or culture detected more

C. difficile

than contact plates. The sensitivity and specificity of a RT-PCR assay for tcdB compared to the culture methods was 76 and 91 %, respectively.

Conclusion. Despite the lower sensitivity and specificity, RT-PCR could potentially offer a more rapid and practical alternative.
Productivity costs associated with reactive school closures related to influenza or influenza-like illness in the United States from 2011 to 2019
Authors: Park Joohyun , Joo Heesoo , Maskery Brian A. , Zviedrite Nicole , Uzicanin Amra
Published: January 2023

Introduction

Schools close in reaction to seasonal influenza outbreaks and, on occasion, pandemic influenza. The unintended costs of reactive school closures associated with influenza or influenza-like illness (ILI) has not been studied previously. We estimated the costs of ILI-related reactive school closures in the United States over eight academic years.

Methods

We used prospectively collected data on ILI-related reactive school closures from August 1, 2011 to June 30, 2019 to estimate the costs of the closures, which included productivity costs for parents, teachers, and non-teaching school staff. Productivity cost estimates were evaluated by multiplying the number of days for each closure by the state- and year-specific average hourly or daily wage rates for parents, teachers, and school staff. We subdivided total cost and cost per student estimates by school year, state, and urbanicity of school location.

Results

The estimated productivity cost of the closures was $476 million in total during the eight years, with most (90%) of the costs occurring between 2016−2017 and 2018−2019, and in Tennessee (55%) and Kentucky (21%). Among all U.S. public schools, the annual cost per student was much higher in Tennessee ($33) and Kentucky ($19) than any other state ($2.4 in the third highest state) or the national average ($1.2). The cost per student was higher in rural areas ($2.9) or towns ($2.5) than cities ($0.6) or suburbs ($0.5). Locations with higher costs tended to have both more closures and closures with longer durations.

Conclusions

In recent years, we found significant heterogeneity in year-to-year costs of ILI-associated reactive school closures. These costs have been greatest in Tennessee and Kentucky and been elevated in rural or town areas relative to cities or suburbs. Our findings might provide evidence to support efforts to reduce the burden of seasonal influenza in these disproportionately impacted states or communities.
Degree of immunoglobulin kappa light chain glycosylation of anti-spike SARS CoV-2 antibodies correlates with COVID-19 severity
Authors: Grigaite Raminta , Iles Jason K , Harding Stephen , Patel Roshani , Wallis Gregg , Iles Ray K
Published: January 2023

Glycosylation of antibodies and the effects this has on inflammatory responses has concentrated predominately on the study of glycosylation moieties found in the Fc region of heavy chains. Light chain glycosylation and their ratios are relatively understudied. Nevertheless, variable glycosylation and ratio of κ and λ light chains have been associated with worse prognosis in myeloma and in tissue deposition – amyloidosis.

The κ & λ light chains, of antibodies binding to SARS-CoV2 nucleocapsid and spike protein were analysed, using MALDI-ToF MS, in respect to their intensity, ratios, glycosylation patterns and any pattern changes correlating with COVID-19 severity. The molecular masses and signal intensity of κ and λ glycosylated and non-glycosylated light chains were measured for immunoglobulins isolated from plasma of sero-positive and sero-negative health care workers (HCW), and convalescent patients who had suffered from acute respiratory distress syndrome (ARDS).

Overall, there was no significant changes in κ to λ ratio of total IgG (via protein G capture) antibodies between the groups. A non-statistically significant trend towards λ light chains was found in antibodies against SARS CoV-2 Nucleocapsid and Spike proteins. However, detailed analysis of the molecular forms found a significant increase and bias towards un-glycosylated light chains and in particular un-glycosylated κ light chains, in antibodies against SAR-CoV-2 spike protein, from convalescent COVID-ARDS patients.

Here we have demonstrated a bias towards un-glycosylated κ chains in anti-spike antibodies in those who suffered from ARDS as a result of SARS-CoV2 infection 3 months after recovery. How this relates to the immunopathology of COVID-19 requires further study.
Improved biorepository to support sickle cell disease genomics and clinical research: A practical approach to link patient data and biospecimens from Muhimbili Sickle Cell Program, Tanzania
Authors: Masamu Upendo , Sangeda Raphael Z , Mgaya Josephine , Nkya Siana , Octavian Beatrice , Mtiiye Frank R , Nduguru Joyce , Jonathan Agnes , Kandonga Daniel , Minja Irene K , Rugajo Paschal , Balandya Emmanuel , Makani Julie
Published: January 2023

Genetic modifiers underlying various sickle cell disease phenotypic expressions are largely unexplored in Africa due to lack of databases linking biospecimens with demographic and clinical data. The problem may be compounded by a complete lack of biorepositories in these settings. This article aims to document the physical verification of biospecimens stored in the biorepository and link them to patient clinical and demographic information to facilitate plans for genomic and related clinical research studies. We reviewed and updated the existing biorepository infrastructure at Muhimbili Sickle Cell Programme in Dar es Salaam, Tanzania. The database of archived biospecimens was updated with the location information of respective biospecimens following the physical verification of biospecimens and then mapping the patient demographic and clinical data with the biospecimen data using sickle cell patients’ demographic identifiers. Three freezers maintained at -80°C store a total of 74,079 biospecimens, of which 63,345 were from 5,159 patients registered in the Muhimbili Sickle Cohort from 2004 to 2016. Out of stored biospecimens, follow-ups were 46,915 (74.06%), control 8,067 (12.74%), admission 5,517 (8.71%) and entry 2,846 (4.49%). Of these registered patients, females were 2,521 (48.87%) and males were 2,638 (51.13%). The age distribution was 1 to 59 years, with those above 18 years being 577 (11.18%) and children 4,582 (88.82%) of registered patients. The notable findings during the process include a lack of automated biospecimen checks, laboratory information management system and standardization of equipment used, biospecimens not linked to clinical and demographic data, date format inconsistencies, lack of regular updating of a database on exhausted biospecimens and updates when biospecimens are moved between positions within freezers. Well-organized biorepository plays a crucial role in answering future research questions. Enforcing strict standard operating procedures and quality control standards will ensure that laboratory scientists and other users adhere to the best biospecimen management procedures.
Effect of experimentally introduced interaural frequency mismatch on sentence recognition in bilateral cochlear-implant listeners
Authors: Cleary Miranda , DeRoy Milvae Kristina , Nguyen Nicole , Bernstein Joshua G. W. , Goupell Matthew J.
Published: January 2023

Bilateral cochlear-implant users experience interaural frequency mismatch because of asymmetries in array insertion and frequency-to-electrode assignment. To explore the acute perceptual consequences of such mismatch, sentence recognition in quiet was measured in nine bilateral cochlear-implant listeners as frequency allocations in the poorer ear were shifted by ±1.5, ±3 and ±4.5 mm using experimental programs. Shifts in frequency allocation >3 mm were found to reduce bilateral sentence scores below those for the better ear alone, suggesting that the poorer ear interfered with better-ear perception. This was not a result of fewer active channels; deactivating electrodes without frequency shifting had minimal effect.
Insufficiency of PCR diagnostics for Detection of DiarrhoeagenicEscherichia coliin Ibadan, Nigeria
Authors: Akinlabi Olabisi C. , Dada Rotimi A. , Nwoko El-shama Q. , Okeke Iruka N.
Published: January 2023

Understanding the contribution of different diarrhoeagenicEscherichia colipathotypes to disease burden is critical to mapping risk and informing vaccine development. Targeting select virulence genes by PCR is the diagnostic approach of choice in high-burden, least-resourced African settings. We compared the performance of a commonly-used multiplex protocol to whole genome sequencing (WGS).

PCR was applied to 3,815E. coliisolates from 120 children with diarrhoea and 357 healthy controls. Three or more isolates per specimen were also Illumina-sequenced. Following quality assurance, ARIBA and Virulencefinder database were used to identify virulence targets. Root cause analysis of deviant PCR results was performed by examining target sensitivity using BLAST, Sanger sequencing false-positive amplicons, and identifying lineages prone to false-positivity using in-silico multilocus sequence typing and a Single Nucleotide Polymorphism phylogeny constructed using IQTree.

The sensitivity and positive predictive value of PCR compared to WGS ranged from 0-77.8% while specificity ranged from 74.5-94.7% for different pathotypes. WGS identified more enteroaggregativeE. coli(EAEC), fewer enterotoxigenicE. coli(ETEC) and none of the Shiga toxin-producingE. colidetected by PCR, painting a considerably different epidemiological picture. Use of the CVD432 target resulted in EAEC under-detection, and enteropathogenicE. coli eaeprimers mismatched more recently described intimin alleles common in our setting. False positive ETEC were over-represented among West Africa-predominant ST8746 complex strains. PCR precision varies with pathogen genome so primers optimized for use in one part of the world may have noticeably lower sensitivity and specificity in settings where different pathogen lineages predominate.
Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases
Authors: Yuan Kai , Longchamps Ryan J. , Pardiñas Antonio F. , Yu Mingrui , Chen Tzu-Ting , Lin Shu-Chin , Chen Yu , Lam Max , Liu Ruize , Xia Yan , Guo Zhenglin , Shi Wenzhao , Shen Chengguo ,   The Schizophrenia Workgroup of Psychiatric Genomics Consortium, Daly Mark J. , Neale Benjamin M. , Feng Yen-Chen A. , Lin Yen-Feng , Chen Chia-Yen , O’Donovan Michael , Ge Tian , Huang Hailiang
Published: January 2023

Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestries has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping, which builds on the single-population fine-mapping framework, Sum of Single Effects (SuSiE). SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and LD patterns, accounts for multiple causal variants in a genomic region, and can be applied to GWAS summary statistics. We comprehensively evaluated SuSiEx using simulations, a range of quantitative traits measured in both UK Biobank and Taiwan Biobank, and schizophrenia GWAS across East Asian and European ancestries. In all evaluations, SuSiEx fine-mapped more association signals, produced smaller credible sets and higher posterior inclusion probability (PIP) for putative causal variants, and captured population-specific causal variants.
Modeling of growth ofUlvasp. macroalgae in a controlled photobioreactor based on nitrogen accumulation dynamics
Authors: Zollmann Meiron , Liberzon Alexander , Golberg Alexander
Published: January 2023

Macroalgae biomass production models that capture nutrient dynamics, temperature, light, and salinity are important for the design and operation of large-scale farms. The goal of this study is to understand how the nitrogen fertilizing regime, relating to fertilizing dose (μM N week-1), amplitude (μM N), and duration (hours), affects the dynamics of nitrogen content and biomass production of theUlvasp. macroalgae. We hypothesize that the nitrogen fertilizing regime controls theUlvaNitrogen Use Efficiency (NUE), defined here as the fraction of fertilizer nitrogen that is utilized and allocated to yield N, and, accordingly, also nitrogen assimilation in the biomass and the growth rate. We test this hypothesis by measuring internal nitrogen and biomass weight and by calculating NUE under various fertilization regimes in controlled photobioreactors. Based on this experimental data, we developed a biomass productivity model that predicts nitrogen and biomass dynamics in time over three weeks of cultivation. This study points out efficient fertilizing regimes and enables the development of a comprehensive understanding of the dynamic relationship between external N, internal N, and biomass production of theUlvasp. macroalgae under varying external N levels, which is important for real-world agricultural applications. This study provides a better understanding of the external N-internal N-biomass triangle followed by an improved dynamic cultivation model, enabling better control of nutrient application and biomass production in macroalgae farming for a sustainable marine bioeconomy.
Temporal Dynamics of Activity in Default Mode Network Suggest a Role in Top-Down Processing for Trial Responses
Authors: Mastrovito D. , Hanson C. , Hanson S.
Published: January 2023

The default mode network (DMN) is a collection of brain regions including midline frontal and parietal structures, medial and lateral temporal lobes, and lateral parietal cortex. Although there is evidence that the network can be subdivided into at least two subcomponents, the network reliably exhibits highly correlated activity both at rest and during task performance. Current understanding regarding the function of the DMN rests on a large body of research indicating that activity in the network decreases during task epochs of experimental paradigms relative to inter-trial intervals. A seeming contradiction arises when the experimental paradigm includes tasks involving autobiographical memory, thinking about one’s self, planning for the future, or social cognition. In such cases, the DMN’s activity increases and is correlated with attentional networks. Some have therefore concluded that the DMN supports advanced human cognitive abilities such as interoceptive processing and theory of mind. This conclusion may be called into question by evidence of correlated activity in homologous brain regions in other, even non-primate, species. Thus, there are contradictory findings related to the function of the DMN that have been difficult to integrate into a coherent theory regarding its function. Using data from the Human Connectome Project, we explore the temporal dynamics of activity in different regions of the DMN in relation to stimulus presentation. We show that generally the dorsal portion of the network exhibits only a transient initial decrease in activity at the start of trials that increases over trial duration. The ventral component often has more similarity in its time course to that of task-activated areas. We propose that task-associated ramping dynamics in the network are incompatible with a task-negative view of the DMN and propose the dorsal and ventral sub-components of network may rather work together to support bottom-up salience detection and subsequent top-down voluntary action. In this context, we re-interpret the body of anatomical and neurophysiological experimental evidence, arguing that this interpretation can accommodate the seeming contradictions regarding DMN function in the extant literature.
Transient septin sumoylation steers a Fir1-Skt5 protein complex between the split septin ring
Authors: Müller Judith , Furlan Monique , Settele David , Grupp Benjamin , Johnsson Nils
Published: January 2023

Ubiquitylation and phosphorylation control composition and architecture of the cell separation machinery in yeast and other eukaryotes. The significance of septin sumoylation on cell separation remained an enigma. Septins form an hourglass structure at the bud neck of yeast cells that transforms into a split septin double ring during mitosis. We discovered that sumoylated septins recruit the cytokinesis checkpoint protein Fir1 to the peripheral side of the septin hourglass. Subsequent de-sumoylation and synchronized binding to the scaffold Spa2 relocate Fir1 in a seamless transition between the split septin rings. Fir1 binds and carries Skt5 on its route to the division plane where the Fir1-Skt5 complex serves as receptor for chitin synthase III. We propose that the opposite positioning of the sumoylated septins and Spa2 creates a tension across the ring that upon de-sumoylation tunnels the membrane-bound Fir1-Skt5 complex through a transiently permeable septin diffusion barrier.
Phage-Assisted, Active Site-Directed Ligand Evolution with a Genetically EncodedNε-Butyryl-L-Lysine to Identify a Cellularly Potent and Selective Inhibitor for the ENL YEATS Domain as an Anti-Leukemia Agent
Authors: Chen Peng-Hsun Chase , Guo Xuejiao Shirley , Zhang Hanyuan Eric , Geng Zhi Zachary , Dubey Gopal K. , Fierke Carol A. , Xu Shiqing , Liu Wenshe Ray
Published: January 2023

Eleven-nineteen leukemia protein (ENL) plays pivotal roles in the leukemogenesis. As a YEATS domain protein, ENL reads histone acylation marks and recruits key transcription factors to leukemic drivers such asHOXA9, MEIS1, andMYBand therefore promotes leukemia development. The histone-reading function of ENL has been proven essential in the onset and progression of several acute leukemias, suggesting a putative therapeutic window for ENL inhibition. In this study, we developed a phage-assisted, active site-directed ligand evolution (PADLE) approach for the identification of potent and selective ENL inhibitors, whereNε-butyryl-l-lysine (BuK) that possesses known target-protein interactions with the ENL YEATS domain was genetically incorporated into a phage display library to serve as a warhead to direct displayed peptides to the active site of ENL YEATS for enrichment. Using this novel strategy in combination with structure-activity relationship that replaced BuK with other ncAAs for de novo π-π-π stacking interactions with two aromatic residues in ENL YEATS, selective and potent ENL inhibitors with aKdvalue as low as 2.0 nM were identified. One pentapeptide inhibitortENL-S1fdisplayed selective inhibition of ENL over other YEATS domains as well as strong cellular target engagement and on-target effects in inhibiting leukemia cell growth and suppressing the expression of ENL target genes. As the first of its kind study, the current work opens a large avenue of research of using PADLE to develop selective and potent peptidyl inhibitors for a large variety of epigenetic reader proteins.
Cortical astrocyte N-Methyl-D-Aspartate receptors influence whisker barrel activity and sensory discrimination
Authors: Ahmadpour Noushin , Kantroo Meher , Stobart Michael J. , Salamovska Tania , O’Hara Finnegan , Erickson Dustin , Carrion-Falgarona Sofia , Stobart Jillian L.
Published: January 2023

Cortical astrocytes encode sensory information through their calcium dynamics, but it remains unclear if modulation of astrocyte calcium transients can change somatosensory circuits and behaviourin vivo. Here, we used a novel knockdown approach to selectively reduce astrocyte N-methyl-D-aspartate receptors (NMDAR). We found that these ionotropic receptors contribute to astrocyte Ca2+transients encoding sensory information. This was essential for the optimal processing of sensory information in nearby neurons, since a reduction in astrocyte NMDARs caused circuit dysfunction and impaired neuronal responses to stimulation. This led to sensory discrimination deficits in the animal. Overall, our findings show that astrocytes can rapidly respond to glutamatergic transmission via their NMDAR and these receptors are an important component for astrocyte-neuron interactions that regulate cortical sensory discriminationin vivo.