bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating angled multimode interferometer with Bragg grating filters for coarse wavelength division (de)multiplexing with optimized shape factor
Authors: Zhang Zanyun , Zhang Wenjing , Jiang Hao , Lv Xiaoqing , Li Meixin , Zhang Kaixin , Liu Tianjun , Huang Beiju
Published: September 2024

We propose and experimentally demonstrate an angled multimode interferometer (AMMI) integrated with cascaded phase-shifted Bragg gratings (PSBGs) for coarse wavelength division multiplexing, based on a 400 nm-thick silicon nitride waveguide platform. Due to the design constraints, the spectral response of a standard AMMI filter suffers from the drawbacks of limited optical bandwidth, high inter-channel crosstalk, and non-ideal shape factor. Two techniques were used to improve performance. Firstly, it was found that increasing the input waveguide width of the AMMI is beneficial for the optical bandwidth while maintaining good insertion loss and crosstalk performance. Experimental results show that the 1 dB bandwidth increases from 7.6 nm to 9.7 nm. To achieve an improved shape factor and decreased crosstalk, the PSBG filters were utilized as the second-stage filters by integrating them at the output waveguides of the AMMI. Simulation results demonstrate an average crosstalk reduction of approximately 15.1 dB at the center wavelengths of the four channels and shape factor improvement by about 0.29. However, measurement results show an average crosstalk decrease of only about 5.5 dB, which is possibly due to the fabrication imperfection of the PSBGs and the unsatisfactory film quality of the SiN wafers used. Despite deviations between measured and simulated performance, the shape factor is increased from 0.26 to 0.74 using these proposed techniques, showing the feasibility of such an integration method.
Polymer dynamics of Alp7A reveals how two critical concentrations govern assembly of dynamically unstable actin-like proteins
Authors: Petek-Seoane Natalie A. , Rodriguez Johnny , Derman Alan I. , Royal Siobhan G. , Lord Samuel J. , Lawrence Rosalie , Pogliano Joe , Mullins R. Dyche
Published: September 2024

Dynamically unstable polymers capture and move cellular cargos in bacteria and eukaryotes, but regulation of their assembly remains poorly understood. Here we describe polymerization of Alp7A, a bacterial actin-like protein (ALP) that distributes copies of plasmid pLS20 among daughter cells in Bacillus subtilis. Purified ATP-Alp7A forms dynamically unstable polymers with a high critical concentration for net assembly (ccN = 10.3 µM), but a much lower critical concentration for filament elongation (ccE = 0.6 µM). Rapid nucleation and stabilization of Alp7A polymers by the accessory factor, Alp7R, decrease ccN into the physiological range. Stable populations of Alp7A filaments appear under two conditions: (i) when Alp7R slows catastrophe rates or (ii) when Alp7A concentrations are high enough to promote filament bundling. These results reveal how dynamic instability maintains high steady-state concentrations of monomeric Alp7A, and how accessory factors regulate Alp7A assembly by modulating ccN independently of ccE.
Prevalence, trends, and outcomes of same-day discharge following elective percutaneous coronary intervention: a retrospective observational cohort study using routinely collected health data
Authors: Chen Yingyan , Smith Ian , Wu Chiung-Jung (Jo) , Hattingh Laetitia , Howes Laurie , Jayasinghe Rohan , Poulter Rohan , Rahman Atifur , Starmer Gregory , Singbal Yash , Yadav Raibhan , Marshall Andrea P
Published: September 2024

Aims

To identify the prevalence, trends, and outcomes of same-day discharge (SDD) following elective percutaneous coronary intervention (PCI) among six public hospitals in Queensland, Australia.

Methods and results

A retrospective observational research design was used. A total of 4387 cases were obtained from the Queensland Cardiac Outcomes Registry and National Hospital Cost Data Collection. The two data sets were linked using identifiable data items. Patients were those who had elective PCI between December 2012 and December 2019 either discharged the same day of the procedure or the next day. Data were analysed using descriptive and inferential statistics. The overall SDD prevalence was 6.5%, with a trend increasing from 0.2% in 2013 to 9.0% in 2019. The prevalence varied at the individual hospital level. Two hospitals did not perform SDD during the study period. The remaining hospitals demonstrated variability in SDD prevalence, with the highest from one hospital being 28.2% in 2019. Almost all SDD patients experienced no complications during or following PCI within 24 h. Compared with next-day discharge, SDD reduced the length of stay by 18 h and conferred an average of $3695 cost-savings per patient.

Conclusion

There was limited implementation of SDD in the six public hospitals contributing data to this study. Improvement in the SDD rate could result in better hospital resource utilization and reduce low-value care. Hence, strategies to implement and promote SDD are warranted.
Evolution of Apoptotic Signaling Pathways Within Lophotrochozoans
Authors: Horkan Helen R , Popgeorgiev Nikolay , Vervoort Michel , Gazave Eve , Krasovec Gabriel
Published: September 2024

Apoptosis is the main form of regulated cell death in metazoans. Apoptotic pathways are well characterized in nematodes, flies, and mammals, leading to a vision of the conservation of apoptotic pathways in metazoans. However, we recently showed that intrinsic apoptosis is in fact divergent among metazoans. In addition, extrinsic apoptosis is poorly studied in non-mammalian animals, making its evolution unclear. Consequently, our understanding of apoptotic signaling pathways evolution is a black box which must be illuminated by extending research to new biological systems. Lophotrochozoans are a major clade of metazoans which, despite their considerable biological diversity and key phylogenetic position as sister group of ecdysozoans (i.e. flies and nematodes), are poorly explored, especially regarding apoptosis mechanisms. Traditionally, each apoptotic signaling pathway was considered to rely on a specific initiator caspase, associated with an activator. To shed light on apoptosis evolution in animals, we explored the evolutionary history of initiator caspases, caspase activators, and the BCL-2 family (which control mitochondrial apoptotic pathway) in lophotrochozoans using phylogenetic analysis and protein interaction predictions. We discovered a diversification of initiator caspases in molluscs, annelids, and brachiopods, and the loss of key extrinsic apoptosis components in platyhelminths, along with the emergence of a clade-specific caspase with an ankyrin pro-domain. Taken together, our data show a specific history of apoptotic actors’ evolution in lophotrochozoans, further demonstrating the appearance of distinct apoptotic signaling pathways during metazoan evolution.
Idiosyncratic genome evolution of the thermophilic cyanobacterium Synechococcus at the limits of phototrophy
Authors: Pierpont C Logan , Baroch Jacob J , Church Matthew J , Miller Scott R
Published: September 2024

Thermophilic microorganisms are expected to have smaller cells and genomes compared with mesophiles, a higher proportion of horizontally acquired genes, and distinct nucleotide and amino acid composition signatures. Here, we took an integrative approach to investigate these apparent correlates of thermophily for Synechococcus A/B cyanobacteria, which include the most heat-tolerant phototrophs on the planet. Phylogenomics confirmed a unique origin of different thermotolerance ecotypes, with low levels of continued gene flow between ecologically divergent but overlapping populations, which has shaped the distribution of phenotypic traits along these geothermal gradients. More thermotolerant strains do have smaller genomes, but genome reduction is associated with a decrease in community richness and metabolic diversity, rather than with cell size. Horizontal gene transfer played only a limited role during Synechococcus evolution, but, the most thermotolerant strains have acquired a Thermus tRNA modification enzyme that may stabilize translation at high temperatures. Although nucleotide base composition was not associated with thermotolerance, we found a general replacement of aspartate with glutamate, as well as a dramatic remodeling of amino acid composition at the highest temperatures that substantially differed from previous predictions. We conclude that Synechococcus A/B genome diversification largely does not conform to the standard view of temperature adaptation. In addition, carbon fixation was more thermolabile than photosynthetic oxygen evolution for the most thermotolerant strains compared with less tolerant lineages. This suggests that increased flow of reducing power generated during the light reactions to an electron sink(s) beyond carbon dioxide has emerged during temperature adaptation of these bacteria.
Excrement and the Construction of the Praying Body in Rabbinic Literature
Authors: Bick Shraga
Published: September 2024

This article addresses the construction of prayer and of the defecating body in rabbinic literature. As opposed to viewing prayer as a spiritual and interior expression of religion and of one’s innermost depths, this study situates prayer within the context of actual bodies—that defecate, flatulate, urinate, spit, and sneeze—precisely at the moment when they wish to stand before the divine. Through a close reading of overlooked meticulous rabbinic discussions regarding cleansing the body before prayer, I examine both the rabbinic theory of prayer as well as the rabbis’ theory of the body while situating their approach within broader perceptions of “bodily bursts” in late antiquity. Instead of an idealized interiority, prominent in contemporary discourses on prayer, the rabbis are engaged in a detailed and ugly examination of their concrete interiority—and with the theological and anthropological meaning of their inability to completely regulate their own bodily activities.
Formalized soundness and completeness of epistemic and public announcement logic
Authors: From Asta Halkjær
Published: September 2024

I strengthen the foundations of epistemic logic by formalizing the family of normal modal logics in the proof assistant Isabelle/HOL. I define an abstract canonical model over any set of axioms and formalize completeness-via-canonicity: when the canonical model for the chosen axioms belongs to a certain class of frames, strong completeness over that class follows immediately. I instantiate the result with logics based on various epistemic principles to obtain completeness results for systems from K to S5. I then move to a family of public announcement logics (PAL) and prove abstract results for strong soundness and completeness. I lift the completeness results from epistemic logic to the setting with public announcements in a modular way. This work formulates the completeness-via-canonicity technique as a proper theorem and demonstrates its applicability. Additionally, it succinctly formalizes the requirements for lifting completeness from bare epistemic logic to the addition of public announcements.
Phylogenomic instructed target analysis reveals ELAV complex binding to multiple optimally spaced U-rich motifs
Authors: McQuarrie David W J , Soller Matthias
Published: September 2024

ELAV/Hu RNA-binding proteins are gene-specific regulators of alternative pre-mRNA processing. ELAV/Hu family proteins bind to short AU-rich motifs which are abundant in pre-mRNA, making it unclear how they achieve gene specificity. ELAV/Hu proteins multimerize, but how multimerization contributes to decode degenerate sequence environments remains uncertain. Here, we show that ELAV forms a saturable complex on extended RNA. Through phylogenomic instructed target analysis we identify the core binding motif U5N2U3, which is repeated in an extended binding site. Optimally spaced short U5N2U3 binding motifs are key for high-affinity binding in this minimal binding element. Binding strength correlates with ELAV-regulated alternative poly(A) site choice, which is physiologically relevant through regulation of the major ELAV target ewg in determining synapse numbers. We further identify a stem–loop secondary structure in the ewg binding site unwound upon ELAV binding at three distal U motifs. Base-pairing of U motifs prevents ELAV binding, but N6-methyladenosine (m6A) has little effect. Further, stem–loops are enriched in ELAV-regulated poly(A) sites. Additionally, ELAV can nucleate preferentially from 3′ to 5′. Hence, we identify a decisive mechanism for ELAV complex formation, addressing a fundamental gap in understanding how ELAV/Hu family proteins decode degenerate sequence spaces for gene-specific mRNA processing.
A GDSL motif-containing lipase modulates Sclerotinia sclerotiorum resistance in Brassica napus
Authors: Ding Li-Na , Hu Ying-Hui , Li Teng , Li Ming , Li Yue-Tao , Wu Yuan-Zhen , Cao Jun , Tan Xiao-Li
Published: September 2024

Sclerotinia stem rot (SSR) caused by Sclerotinia sclerotiorum (Lib.) De Bary is a devastating disease infecting hundreds of plant species. It also restricts the yield, quality, and safe production of rapeseed (Brassica napus) worldwide. However, the lack of resistance sources and genes to S. sclerotiorum has greatly restricted rapeseed SSR-resistance breeding. In this study, a previously identified GDSL motif-containing lipase gene, B. napus GDSL LIPASE-LIKE 1 (BnaC07.GLIP1), encoding a protein localized to the intercellular space, was characterized as functioning in plant immunity to S. sclerotiorum. The BnaC07.GLIP1 promoter is S. sclerotiorum-inducible and the expression of BnaC07.GLIP1 is substantially enhanced after S. sclerotiorum infection. Arabidopsis (Arabidopsis thaliana) heterologously expressing and rapeseed lines overexpressing BnaC07.GLIP1 showed enhanced resistance to S. sclerotiorum, whereas RNAi suppression and CRISPR/Cas9 knockout B. napus lines were hyper-susceptible to S. sclerotiorum. Moreover, BnaC07.GLIP1 affected the lipid composition and induced the production of phospholipid molecules, such as phosphatidylethanolamine, phosphatidylcholine, and phosphatidic acid, which were correlated with decreased levels of reactive oxygen species (ROS) and enhanced expression of defense-related genes. A B. napus bZIP44 transcription factor specifically binds the CGTCA motif of the BnaC07.GLIP1 promoter to positively regulate its expression. BnbZIP44 responded to S. sclerotiorum infection, and its heterologous expression inhibited ROS accumulation, thereby enhancing S. sclerotiorum resistance in Arabidopsis. Thus, BnaC07.GLIP1 functions downstream of BnbZIP44 and is involved in S. sclerotiorum resistance by modulating the production of phospholipid molecules and ROS homeostasis in B. napus, providing insights into the potential roles and functional mechanisms of BnaC07.GLIP1 in plant immunity and for improving rapeseed SSR disease-resistance breeding.
Diagnostic Delay in Patients from the International Map of Axial Spondyloarthritis: Geographic, Sociodemographic and Disease-related factors
Authors: Poddubnyy Denis , Garrido-Cumbrera Marco , Sommerfleck Fernando , Navarro-Compán Victoria , Bundy Christine , Makri Souzi , Correa-Fernández José , Akerkar Shashank , Davies Jo , Karam Elie
Published: September 2024

Objectives

To assess diagnostic delay and its associated factors globally, in a large sample of patients included in the International Map of Axial Spondyloarthritis (IMAS).

Methods

IMAS is a cross-sectional online survey (2017–22) of 5557 axial spondyloarthritis (axSpA) patients from 27 countries. Diagnostic delay was calculated as the difference between age at diagnosis and age at first symptom onset reported by patients. Associations between diagnostic delay and regions, sociodemographic characteristics and disease-related factors were explored through univariable and multivariable linear regression analysis.

Results

Data from 5327 patients who reported data on diagnostic delay in IMAS survey were analysed: 3294 were from Europe, 752 from North America, 590 from Asia, 545 from Latin America and 146 from Africa. Overall, patients reported a mean diagnostic delay of 7.4 years (median: 4.0) since symptom onset, with substantial variation across regions; the highest delay was in South Africa and the lowest in Asia. The variables associated with longer diagnostic delay in the final multivariable regression model were: younger age at symptom onset (b = –0.100), female gender (b = 2.274), being diagnosed by a rheumatologist (b = 1.163), greater number of heathcare professionals (HCPs) seen before diagnosis (b = 1.033) and history of uveitis (b = 1.286).

Conclusion

In this global sample of axSpA patients the mean diagnostic delay was 7.4 years, and showed significant differences across regions. Younger age at symptom onset, female gender, diagnosis made by a rheumatologist, greater number of HCPs seen before diagnosis and history of uveitis were the parameters associated with a longer diagnostic delay in axSpA patients.
RNA-Sequencing-Based Virome Discovery in Florida Citrus Pests
Authors: Britt-Ugartemendia Kellee , Stevens Kristian , Al Rwahnih Maher , Levy Amit , Batuman Ozgur
Published: September 2024

The widespread devastation from Huanglongbing (HLB), also known as citrus greening, and several damaging insect pests continue to hamper Florida citrus growers, and environmentally harmful insecticides require adequate control. Repeated applications of these insecticides for sufficient control spurred research interest in insect-specific viruses (ISVs). ISVs used as a biocontrol may offer growers increased specificity of insect targets and the genomic potential for lethal modifications. To discover prospective ISVs of these citrus pests, we employed high-throughput sequencing (HTS), which has revolutionized virome studies of these biological organisms. With the intent to increase our source of potential viruses for future bio-insecticidal purposes, we used HTS. We screened for novel ISVs within seven economically destructive Florida citrus pests, specifically the black citrus aphid (Aphis aurantii), green citrus (or spirea) aphid (Aphis spiraecola), Asian citrus psyllid (Diaphorina citri; ACP), citrus leafminer (Phyllocnistis citrella), brown soft scale (Coccus hesperidum), Florida wax scale (Ceroplastes floridensis), and the sharp-nosed leafhopper (Scaphytopius spp.). Most insects in this study originated from citrus grove populations, while some were collected from rutaceous greenhouse plants. For ACP, the insect vector transmitting the bacterial agent of HLB, Candidatus Liberibacter asiaticus, we investigated differences in presumptive ISV profiles between laboratory and field-collected populations and nymph versus adult populations. Ten putative, novel viral sequences were discovered and characterized collectively from these pests. Overall, this study contributes to the cumulative knowledge of ISVs associated with diverse insect populations, uncovers resources for future downstream bio-insecticidal modifications, and illuminates the ongoing viral diversity still in need of investigation.
Development of a Recombinase Polymerase Amplification Assay for Rapid Detection of the New Root-lesion Nematode Pratylenchus dakotaensis on Soybean
Authors: Dhakal Roshan , Chowdhury Intiaz Amin , Plaisance Addison , Yan Guiping
Published: September 2024

Root-lesion nematodes, Pratylenchus spp. are reported to cause serious yield losses in various crops including soybean. A new root-lesion nematode species was recently detected in a soybean field in North Dakota (ND) and named Pratylenchus dakotaensis. Nematode detection and differentiation from other species are critical in management strategies. Thus, a recombinase polymerase amplification (RPA) assay was developed for rapid detection of this nematode from field soils under isothermal conditions. New primers and probes were designed from ITS-rDNA region of the nematode genome and tested for both specificity and sensitivity. The RPA assay was able to detect DNA from a single adult nematode at 39.5°C in 20 minutes using both Basic and Exo kits. The specificity of the primers was initially confirmed through in silico analyses, followed by laboratory tests. The assay successfully amplified DNA from the target species, while no amplification occurred for other Pratylenchus spp. and non-Pratylenchus control species. Sensitivity testing with real-time RPA revealed its ability to detect DNA in dilutions equivalent to 1/32 of a single nematode from DNA extracted from inoculated sterile soil. To further validate the assay, it was tested with 19 field soil samples collected in ND. This assay amplified soil DNA extracts of all P. dakotaensis-infested field samples confirmed through conventional PCR. It did not amplify DNA from 13 other field soils infested with other Pratylenchus spp. This is the first report of RPA develoment for detecting a root-lesion nematode species. The RPA assay developed can help in the rapid detection of this nematode species for effective nematode management.
A New Threat to Limber Pine (Pinus flexilis) Restoration in Alberta and Beyond: First Documentation of a Cronartium ribicola Race (vcr4) Virulent to Cr4-Controlled Major Gene Resistance
Authors: Liu Jun-Jun , Sniezko Richard A. , Houston Sydney , Alger Genoa , Krakowski Jodie , Schoettle Anna W. , Sissons Robert , Zamany Arezoo , Williams Holly , Rancourt Benjamin , Kegley Angelia
Published: September 2024

The coevolution of virulence reduces the effectiveness of host resistance to pathogens, posing a direct threat to forest species and their key ecosystem functions. This is a threat to limber pine ( Pinus flexilis), an endangered species in Canada due to rapid decline mainly driven by white pine blister rust caused by Cronartium ribicola. We present the first report of a new, virulent race of C. ribicola (designated vcr4) that overcomes limber pine major gene ( Cr4) resistance (MGR). Field surveys found that three parental trees (pf-503, pf-508, and pf-2015-0070) were cankered with white pine blister rust in Alberta, but their progenies showed MGR-related phenotypic segregation postinoculation with an avirulent race of C. ribicola ( Avcr4). Genotyping of their progenies using Cr4-linked DNA markers and a genome-wide association study provided additional support that these cankered parental trees had Cr4-controlled MGR. To confirm the presence of vcr4, aeciospores were collected from the cankered pf-503 tree to inoculate resistant seedlings that had survived prior inoculation using the Avcr4 race, as well as seedlings of two U.S. seed parents, one previously confirmed with MGR ( Cr4) and one without MGR, respectively. All inoculated seedlings showed clear stem symptoms, confirming that the virulent race is vcr4. These results provide insights into the evolution of C. ribicola virulence and reinforce caution on deployment of Cr4-controlled MGR. The information will be useful for designing a breeding program for durable resistance by layering both R genes with quantitative trait loci for resistance to white pine blister rust in North America.
Assessment of Racial Bias within the Risk Analysis Index of Frailty
Authors: Jacobs Michael A. , Hausmann Leslie R. M. , Handzel Robert M. , Schmidt Susanne , Jacobs Carly A. , Hall Daniel E.
Published: September 2024

Objective:

Our objective was to assess potential racial bias within the Risk Analysis Index (RAI).

Background:

Patient risk measures are rarely tested for racial bias. Measures of frailty, like the RAI, need to be evaluated for poor predictive performance among Black patients.

Methods:

Retrospective cohort study using April 2010–March 2019 Veterans Affairs Surgical Quality Improvement Program and 2010–2019 National Surgical Quality Improvement Program data. The performance of the RAI and several potential variants were compared between Black and White cases using various metrics to predict mortality (180-day for Veterans Affairs Surgical Quality Improvement Program, 30-day for National Surgical Quality Improvement Program).

Results:

Using the current, clinical threshold, the RAI performed as good or better among Black cases across various performance metrics versus White. When a higher threshold was used, Black cases had higher true positive rates but lower true negative rates, yielding 2.0% higher balanced accuracy. No RAI variant noticeably eliminated bias, improved parity across both true positives and true negatives, or improved overall model performance.

Conclusions:

The RAI tends to predict mortality among Black patients better than it predicts mortality among White patients. As existing bias-reducing techniques were not effective, further research into bias-reducing techniques is needed, especially for clinical risk predictions. We recommend using the RAI for both statistical analysis of surgical cohorts and quality improvement programs, such as the Surgical Pause.
Accelerated Wean: A Novel 3 Day Berlin Heart Protocol in a Pediatric Patient
Authors: Subramanian Sujata , Ponce-Rivera Monica S. , Affolter Jeremy , Shmorhun Daniel , Owens Richard , Fraser Charles D. , Glass Lauren
Published: September 2024

We present the case of a 4 year old child who developed cardiogenic shock due to permanent junctional reciprocating tachycardia, requiring left ventricular assist device (LVAD) support. Despite the initial critical clinical presentation, successful myocardial recovery was achieved over 5 months, allowing for successful LVAD explantation. The patient’s young age and behavioral issues were constraining factors for a prolonged LVAD wean trial. A modified wean protocol over a 3 day period with parameters for assessment of cardiac recovery before LVAD explantation is described.
Modernizing Public Health Data Systems and Workforce Capacity: The Centers for Disease Control and Prevention’s Public Health Informatics Fellowship Program
Authors: Kirkcaldy Robert D. , Biggers Bradley , Bonney Wilfred , Gordon Jeffrey , Yassine Brianne , Crawford Brandi , Papagari Sangareddy Sridhar , Franzke Laura , Bernstein Kyle T.
Published: September 2024

Context:

The COVID-19 pandemic exposed governmental public health’s outdated information technology and insufficient data science and informatics workforce capacity. The Centers for Disease Control and Prevention’s Public Health Informatics Fellowship Program (PHIFP) is well positioned to strengthen public health data science and informatics workforce capacity.

Program:

Established in 1996, PHIFP is a 2-year, full-time, on-the-job training program. PHIFP includes a didactic curriculum, applied learning through informatics projects completed at the assigned host site, short-term technical assistance projects, and a final capstone project.

Evaluation:

Fellows have learned from and bolstered host site informatics capacity through the development or enhancement of information systems, evaluations, data integration, data visualization, and analysis. Among recent graduates, 54% are employed at Centers for Disease Control and Prevention and 16% are employed at other public health organizations, including local health departments.

Discussion:

Fellowships such as PHIFP, which recruit and train promising scientists in public health informatics, are important components of efforts to strengthen public health workforce capacity.
Predicting Gene Comutation of EGFR and TP53 by Radiomics and Deep Learning in Patients With Lung Adenocarcinomas
Authors: Wang Xiao-yan , Wu Shao-hong , Ren Jiao , Zeng Yan , Guo Li-li
Published: September 2024

Purpose:

This study was designed to construct progressive binary classification models based on radiomics and deep learning to predict the presence of epidermal growth factor receptor (EGFR) and TP53 mutations and to assess the models’ capacities to identify patients who are suitable for TKI-targeted therapy and those with poor prognoses.

Materials and Methods:

A total of 267 patients with lung adenocarcinomas who underwent genetic testing and noncontrast chest computed tomography from our hospital were retrospectively included. Clinical information and imaging characteristics were gathered, and high-throughput feature acquisition on all defined regions of interest (ROIs) was carried out. We selected features and constructed clinical models, radiomics models, deep learning models, and ensemble models to predict EGFR status with all patients and TP53 status with EGFR-positive patients, respectively. The validity and reliability of each model were expressed as the area under the curve (AUC), sensitivity, specificity, accuracy, precision, and F1 score.

Results:

We constructed 7 kinds of models for 2 different dichotomies, namely, the clinical model, the radiomics model, the DL model, the rad-clin model, the DL-clin model, the DL-rad model, and the DL-rad-clin model. For EGFR− and EGFR+, the DL-rad-clin model got the highest AUC value of 0.783 (95% CI: 0.677-0.889), followed by the rad-clin model, the DL-clin model, and the DL-rad model. In the group with an EGFR mutation, for TP53− and TP53+, the rad-clin model got the highest AUC value of 0.811 (95% CI: 0.651-0.972), followed by the DL-rad-clin model and the DL-rad model.

Conclusion:

Our progressive binary classification models based on radiomics and deep learning may provide a good reference and complement for the clinical identification of TKI responders and those with poor prognoses.
Characterization of a mammalian orthoreovirus isolated from the large flying fox, Pteropus vampyrus, in Indonesia
Authors: Intaruck Kittiya , Tabata Koshiro , Itakura Yukari , Kawaguchi Nijiho , Kishimoto Mai , Setiyono Agus , Handharyani Ekowati , Harima Hayato , Kimura Takashi , Hall William W. , Orba Yasuko , Sawa Hirofumi , Sasaki Michihito
Published: September 2024

Fruit bats serve as an important reservoir for many zoonotic pathogens, including Nipah virus, Hendra virus, Marburg virus and Lyssavirus. To gain a deeper insight into the virological characteristics, pathogenicity and zoonotic potential of bat-borne viruses, recovery of infectious viruses from field samples is important. Here, we report the isolation and characterization of a mammalian orthoreovirus (MRV) from a large flying fox (Pteropus vampyrus) in Indonesia, which is the first detection of MRV in Southeast Asia. MRV was recovered from faecal samples of three different P. vampyrus in Central Java. Nucleotide sequence analysis revealed that the genome of the three MRV isolates shared more than 99% nucleotide sequence identity. We tentatively named one isolated strain as MRV12-52 for further analysis and characterization. Among 10 genome segments, MRV12-52 S1 and S4, which encode the cell-attachment protein and outer capsid protein, had 93.6 and 95.1% nucleotide sequence identities with known MRV strains, respectively. Meanwhile, the remaining genome segments of MRV12-52 were divergent with 72.9–80.7 % nucleotide sequence identities. Based on the nucleotide sequence of the S1 segment, MRV12-52 was grouped into serotype 2, and phylogenetic analysis demonstrated evidence of past reassortment events. In vitro characterization of MRV12-52 showed that the virus efficiently replicated in BHK-21, HEK293T and A549 cells. In addition, experimental infection of laboratory mice with MRV12-52 caused severe pneumonia with 75% mortality. This study highlights the presence of pathogenic MRV in Indonesia, which could serve as a potential animal and public health concern.
Identification of a cooperative effect between amino acids 169 and 174 in the rotavirus NSP4 double-layered particle-binding domain
Authors: Herbert Jayme , van Dijk Alberdina A.
Published: September 2024

Segmented RNA viruses are capable of exchanging genome segments via reassortment as a means of immune evasion and to maintain viral fitness. Reassortments of single-genome segments are common among group A rotaviruses. Multiple instances of co-reassortment of two genome segments, GS6(VP6) and GS10(NSP4), have been documented in surveillance. Specifically, a division between NSP4 genotypes has been observed in the NSP4 double-layered particle (DLP)-binding domain. A previously hypothesized mechanism for this co-reassortment has been suggested to be the interaction between VP6 and NSP4 during DLP transport from viroplasms for particle maturation. In this study, we used sequence analysis, RNA secondary structure prediction, molecular dynamics and reverse genetics to form a hypothesis regarding the role of the NSP4 DLP-binding domain. Sequence analysis showed that the polarity of NSP4 DLP-binding domain amino acids 169 and 174 is clearly divided between E1 and E2 NSP4 genotypes. Viruses with E1 NSP4s had 169A/I or 169S/T with 174S. E2 NSP4s had 169R/K and 174A. RNA secondary structure prediction showed that mutation in both 545 (aa169) and 561 (aa174) causes global structure remodelling. Molecular dynamics showed that the NSP4/VP6 interaction stability is increased by mutating both aa positions 169 and 174. Using reverse genetics, we showed that an R169I mutation alone does not prevent rescue. Conversely, 174A to 174S prevented rescue, and rescue could be returned by combining 174S with 169I. When compared to rSA11 NSP4-wt, both rSA11 NSP4-R169I and rSA11 NSP4-R169I/A174S had a negligible but significant reduction in titre at specific time points. This study suggests that amino acid 174 of NSP4 may be essential in maintaining the VP6/NSP4 interaction required for DLP transport. Our results suggest that maintenance of specific polarities of amino acids at positions 169 and 174 may be required for the fitness of rotavirus field strains.
Development of novel broad-range pan-genus PCR assays for the detection of Tropheryma species
Authors: Tagini Florian , Belkoniene Mhedi , Jaton Katia , Opota Onya , Greub Gilbert
Published: September 2024

Introduction.
Tropheryma whipplei is responsible for the classical Whipple’s disease. Recently, a new Tropheryma species was described in a Belgian immunocompromised patient with pleuritis.

Gap Statement. There is currently no specific molecular diagnostic test detecting other Tropheryma species than Tropheryma whipplei.

Aim. To develop and validate two broad-range pan-Tropheryma genus PCRs detecting both T. whipplei and new Tropheryma species.

Methodology. From shotgun sequencing data of the lung tissue biopsy of the Belgian subject, we designed two PCRs targeting the 23S rRNA and rnpB genes. Prospectively, requests for T. whipplei PCR were tested with T. whipplei-specific PCRs and the two Tropheryma broad-range PCRs from January 2019 to November 2022.

Results. In total, 2605 samples were tested using both the pan-Tropheryma 23S rRNA PCR and the T. whipplei-specific PCR. In addition, 833 of the 2605 samples were also tested using the pan-Tropheryma rnpB PCRs. Sensitivity was 78.8% and 79.7% for 23S rRNA and rnpB PCRs, as compared with the species-specific T. whipplei PCR. Specificity was 99.9% and 99.7% for the 23S rRNA and the rnpB PCRs, respectively. We identified a patient whose bronchoalveolar lavage tested positive with the two broad-range PCRs with >105 copies ml−1. Specific T. whipplei PCRs were negative. Known for panuveitis, this 49-year-old male presented with an eye inflammation recurrence, and a CT scan showed multiple mediastino-hilar necrotic adenopathies. Doxycyclin (1 year), hydroxychloroquin (1 year) and co-trimoxazol (1 month) treatments led to a favourable outcome.

Conclusion. Specific T. whipplei PCR exhibited better sensitivity than the pan-Tropheryma PCRs. However, both broad-range pan-Tropheryma PCRs demonstrated excellent specificity and were pivotal to identifying a new probable case of Tropheryma infection due to another species-level lineage.
A Genome-wide Association Study Identifies Novel Genetic Variants Associated with Knee Pain in the UK Biobank (N = 441,757)
Authors: Tao Yiwen , Pan Qi , cai tengda , Yang Luning , haque mainul , dottorini tania , Meng Weihua
Published: September 2024

Knee pain is a widespread musculoskeletal condition affecting millions globally, with significant socio-economic implications. This study endeavors to identify genetic variants associated with knee pain through a comprehensive genome-wide association study (GWAS) using data from 441,757 individuals in the UK Biobank. The primary GWAS identified ten significant loci, including eight novel loci, with the most significant single nucleotide polymorphism (SNP) being rs143384 near theGDF5gene on chromosome 20 (p= 4.68 x 10-19). In the replication study, seven loci (rs143384, rs919642, rs55760279, rs56076919, rs3892354, rs687878, rs368636424) were found to be significant in the FinnGen cohort. Further, sex-specific analyses revealed distinct genetic associations, identifying three loci (rs143384 withp= 1.70x10-15, rs56076919 withp= 1.60x10-9, rs919642 withp= 1.45x10-8) in females and four loci ( rs2899611 withp= 2.77 x 10-11, rs891720 withp= 5.55 x 10-11, rs2742313 withp= 4.19 x 10-9, rs2019689 withp= 6.51 x 10-9) in males. The phenome-wide association analysis and Mendelian randomization analysis revealed significant links between several phenotypes and knee pain such as leg pain on walking. These findings enhance our understanding of the genetic factors of knee pain, offering potential pathways for therapeutic interventions and personalized medical strategies.
RSV healthcare burden in adults before and since the emergence of the COVID-19 pandemic in 6 European countries
Authors: Urchueguía-Fornes Arantxa , Osei-Yeboah Richard , Jollivet Ombeline , Johannesen Caroline Klint , Lehtonen Toni , van Boven Michiel , Gideonse David , Cohen Rachel A. , Orrico-Sánchez Alejandro , Kramer Rolf , Fischer Thea K. , Heikkinen Terho , Nair Harish , Campbell Harry ,   PROMISE investigators
Published: September 2024

Introduction

Respiratory Syncytial Virus (RSV) is a major cause of morbidity in older adults. With the emergence of the coronavirus disease 2019 (COVID-19) and the subsequent changes in respiratory viral circulation, it is crucial to reassess RSV-associated healthcare burden in adults. This study assessed RSV-associated healthcare burden in adults in six European countries before and during the COVID-19 pandemic.

Methods

We conducted a retrospective analysis using national hospital admissions data from Denmark, England, Finland, the Netherlands, Scotland, and regional surveillance data from the Valencia region (Spain). We included patients aged ≥18 years hospitalised for respiratory tract infections (RTIs) from 2016 to 2023. We assessed RSV-coded and laboratory-confirmed hospitalisations, intensive care unit (ICU) admissions, in-hospital length of stay (LOS), and mortality.

Results

RSV-associated hospitalisations significantly reduced during the 2020/2021 season across all countries, coinciding with strict COVID-19 preventive measures, but resurged in subsequent seasons. We observed the highest hospitalisation rates in adults aged ≥85 years. RSV-coded hospitalisations were found to underestimate the true burden when compared with laboratory-confirmed cases. Underestimation factors ranged from 1.1 to 4.3 times across countries. No significant differences were observed in LOS or ICU admission rates for RSV-associated hospitalisations compared to RTIs.

Discussion

Our findings underscore the complex epidemiology of RSV in older adults. The differences between RSV-coded and laboratory-confirmed cases highlight the critical need for improved surveillance and diagnostic practices to better assess the true burden. Our findings could be vital for guiding public health strategies, particularly with the recent introduction of RSV vaccines for older adults.
A neural mechanism for compositional generalization of structure in humans
Authors: Luettgau Lennart , Chen Nan , Erdmann Tore , Veselic Sebastijan , Moran Rani , Kurth-Nelson Zeb , Dolan Raymond J.
Published: September 2024

An exceptional human ability to adapt to the dynamics of novel environments relies on abstracting and generalizing past experiences. While previous research has examined how humans generalize isolated sequential processes, we know little concerning the neural mechanisms that enable adaptation to the more complex dynamics that govern everyday experience. Here, we deployed a novel sequence learning task based on graph factorization, coupled with simultaneous magnetoencephalography (MEG) recordings, to ask whether reuse of experiential “building blocks” provides an abstract structural scaffolding that enables inference and generalization. We provide behavioral evidence that participants decomposed task experience into subprocesses, abstracted dynamical subprocess structures away from sensory specifics, and transferred these to a new task environment. Neurally we show this transfer is underpinned by a representational alignment of abstract subprocesses across task phases, where this included enhanced neural similarity among stimuli that adhered to the same subprocess, a temporally evolving mapping between predictive representations of subprocesses and a generalization of the precise dynamical roles that stimuli occupy within graph structures. Crucially, decoding strength for dynamical role representations predicted behavioral success in transfer of subprocess knowledge, consistent with a role in supporting behavioral adaptation in new environments. We propose a structural scaffolding mechanism enables compositional generalization of dynamical subprocesses that facilitate efficient adaptation within new contexts.
Are Electromyography data a fingerprint for patients with cerebral palsy (CP)?
Authors: Davoudi Mehrdad , Salami Firooz , Reisig Robert , Patikas Dimitrios A. , Beckmann Nicholas A. , Gather Katharina Susanne , Wolf Sebastian I.
Published: September 2024

This study aimed to first investigate changes in electromyography (EMG) patterns after multilevel surgical treatment in patients with cerebral palsy (CP) and then to assess the connection between the measure of EMG and motor control indices and surgery outcomes. We analyzed retrospective EMG and gait data from 167 patients with CP before and after surgery and from 117 typically developed individuals as a reference group. The patients underwent at least one soft tissue surgery on their shank and foot muscles. Using Repeated Measures ANOVA, we examined the norm-distance (ND) of the kinematics, kinetics, and EMG patterns, in addition to the Kerpape-Rennes EMG-based Gait Index (EDI), EMG Profile Score (EPS), and Walking Dynamic Motor Control Index (DMC) before and after surgery. Participants were divided into different response groups (Poor, Mild, and Good gait quality) according to their pre- and post-treatment Gait Deviation Index (GDI), using the K-means-PSO clustering algorithm. The gait and EMG indices were compared between the responders using the nonparametric Mann-Whitney test. The ND for all kinematics and kinetics parameters significantly improved (p-value < 0.05) after the surgery. Regarding EMG, a significant reduction was only observed in the ND of the rectus femoris (p-value < 0.001) and soleus (p-value = 0.006). Among the indices, DMC was not altered post-operatively (p-value = 0.88). Although EDI and EPS were consistent across responders with a similar pre-treatment gait, a higher DMC was significantly associated with a greater improvement, particularly in patients with poor gait (p-value < 0.05). These findings indicate systematic changes in the EMG of patients with CP following surgery, which can also be demonstrated through indices. DMC is a measure that can potentially serve as a partial predictor of outcomes, particularly in patients with poor pre-operative gait. Future research should investigate the effects of different surgical strategies on the improvement of these patients.
Language Modeling Screens Parkinson’s Disease with Self-reported Questionnaires
Authors: Machado Reyes Diego , Hahn Juergen , Shen Li , Yan Pingkun
Published: September 2024

Parkinson’s disease (PD) is a growing public health challenge associated with the aging population. Current diagnostic methods rely on motor symptoms and invasive procedures, making early detection difficult. This study established a transferable artificial intelligence (AI) model, Quest2Dx, to analyze health questionnaires to enable low-cost and non-invasive PD diagnosis. Quest2Dx tackles the common challenges of missing responses and required specific modeling for each questionnaire by developing a novel language modeling approach to allow the model transfer across different questionnaires and to enhance the interpretability. Evaluated on the PPMI and Fox Insight datasets, Quest2Dx achieved AUROCs of 0.977 and 0.974, respectively, significantly outperforming existing methods. Additionally, cross-questionnaire validation achieved AUROCs of 0.920 and 0.952, respectively, from PPMI to Fox Insight and vice versa. Quest2Dx also identified key predictors from the list of questions to provide further insights. The validated technology elucidates a promising path for PD screening in primary-care settings.
Indirect costs and scientific impact at NIMH
Authors: Perlis Roy H.
Published: September 2024

The National Institutes of Health (NIH) awards additional funds for extramural research to support research infrastructure and administration, such that the total cost of a given research project depends on where it is conducted. We sought to understand whether greater indirects were associated with a greater scientific impact of NIH-funded work. The NIH RePORTER database was queried to retrieve all R01, R21, or R03-funded research proposals for which NIMH was listed as the primary funding source for proposals funded between 2012 and 2023. We applied multiple regression to examine the association between indirect rate and measures of scientific impact, including number of publications, their citation impact in terms of H-index per grant and total citations, and the number of patents associated with each grant. Of 5,143 projects, reflecting $9.85 billion, mean indirect rate was 47.9% (SD 16.2%). Greater indirect rate was associated with modest but statistically significantly greater number of publications (+0.30 per 10% increase in indirect rate, 95% CI 0.08-0.51); H-index at 5 years (+0.25 per 10% increase in indirect rate, 95% CI 0.18-0.33; Figure 1); and total citations (+29.71 per 10% increase in indirect rate, 95% CI 17.86-41.57). Each 10% increase in indirect rate was associated with a 20% increase in odds of patent filing (aOR 1.20, 95% CI 1.05-1.37). The results suggest small incremental benefits from conduct of research at higher-cost institutions and provide data for policymakers to consider in weighing the costs against potential benefits of work at such institutions.