bluuebunny/crossref_metadata_2025 huggingface dataset:
An upper bound for the rational topological complexity of a family of elliptic spaces
Authors: Hamoun Said , Rami Youssef , Vandembroucq Lucile
Published: October 2024

In this work, we show that, for any simply-connected elliptic space

S
S

admitting a pure minimal Sullivan model with a differential of constant length, we have

T

C
0

(
S
)
≤
2
c
a

t
0

(
S
)
+

χ

π

(
S
)

TC_0(S)\leq 2cat_0(S)+\chi _{\pi }(S)

where

T

C
0

(
S
)

TC_0(S)

and

c
a

t
0

(
S
)

cat_0(S)

denote respectively the rational topological complexity and Lusternik-Schnirelmann category, and

χ

π

(
S
)

\chi _{\pi }(S)

is the homotopy characteristic of

S
S

. This is obtained by establishing a structure theorem showing that such a space can be rationally realized as the total space of a fibration over an

F
0

F_0

-space with fibre a product of odd-dimensional spheres.
ULTRA-effective labeling of tandem repeats in genomic sequence
Authors: Olson Daniel R , Wheeler Travis J
Published: October 2024

In the age of long read sequencing, genomics researchers now have access to accurate repetitive DNA sequence (including satellites) that, due to the limitations of short read-sequencing, could previously be observed only as unmappable fragments. Tools that annotate repetitive sequence are now more important than ever, so that we can better understand newly uncovered repetitive sequences, and also so that we can mitigate errors in bioinformatic software caused by those repetitive sequences. To that end, we introduce the 1.0 release of our tool for identifying and annotating locally repetitive sequence, ULTRA Locates Tandemly Repetitive Areas (ULTRA). ULTRA is fast enough to use as part of an efficient annotation pipeline, produces state-of-the-art reliable coverage of repetitive regions containing many mutations, and provides interpretable statistics and labels for repetitive regions.

Availability and implementation

ULTRA is released under an open source license, and is available for download at https://github.com/TravisWheelerLab/ULTRA.
MSDAFL: molecular substructure-based dual attention feature learning framework for predicting drug–drug interactions
Authors: Hou Chao , Duan Guihua , Yan Cheng
Published: October 2024

Motivation

Drug–drug interactions (DDIs) can cause unexpected adverse drug reactions, affecting treatment efficacy and patient safety. The need for computational methods to predict DDIs has been growing due to the necessity of identifying potential risks associated with drug combinations in advance. Although several deep learning methods have been recently proposed to predict DDIs, many overlook feature learning based on interactions between the substructures of drug pairs.

Results

In this work, we introduce a molecular Substructure-based Dual Attention Feature Learning framework (MSDAFL), designed to fully utilize the information between substructures of drug pairs to enhance the performance of DDI prediction. We employ a self-attention module to obtain a set number of self-attention vectors, which are associated with various substructural patterns of the drug molecule itself, while also extracting interaction vectors representing inter-substructure interactions between drugs through an interactive attention module. Subsequently, an interaction module based on cosine similarity is used to further capture the interactive characteristics between the self-attention vectors of drug pairs. We also perform normalization after the interaction feature extraction to mitigate overfitting. After applying three-fold cross-validation, the MSDAFL model achieved average precision scores of 0.9707, 0.9991, and 0.9987, and area under the receiver operating characteristic curve scores of 0.9874, 0.9934, and 0.9974 on three datasets, respectively. In addition, the experiment results of five-fold cross-validation and cross-datum study also indicate that MSDAFL performs well in predicting DDIs.

Availability and implementation

Data and source codes are available at https://github.com/27167199/MSDAFL.
RTF: an R package for modelling time course data
Authors: Brombacher Eva , Kreutz Clemens
Published: October 2024

The retarded transient function (RTF) approach serves as a complementary method to ordinary differential equations (ODEs) for modelling dynamics typically observed in cellular signalling processes. We introduce an R package that implements the RTF approach, originally implemented within the MATLAB-based Data2Dynamics modelling framework. This package facilitates the modelling of time and dose dependencies, and it includes the possibility of model reduction to minimize overfitting. It can be applied to experimental data or trajectories of ODE models to characterize their dynamics. Additionally, it can generate a low-dimensional representation based on the fitted RTF parameters of a set of time-resolved data, aiding in the identification of key targets of experimental perturbations.

Availability and implementation

The R package RTF is available at https://github.com/kreutz-lab/RTF.
The use of 7T MRI in multiple sclerosis: review and consensus statement from the North American Imaging in Multiple Sclerosis Cooperative
Authors: Harrison Daniel M , Sati Pascal , Klawiter Eric C , Narayanan Sridar , Bagnato Francesca , Beck Erin S , Barker Peter , Calvi Alberto , Cagol Alessandro , Donadieu Maxime , Duyn Jeff , Granziera Cristina , Henry Roland G , Huang Susie Y , Hoff Michael N , Mainero Caterina , Ontaneda Daniel , Reich Daniel S , Rudko David A , Smith Seth A , Trattnig Siegfried , Zurawski Jonathan , Bakshi Rohit , Gauthier Susan , Laule Cornelia
Published: October 2024

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology’s promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS.
Treatment of pemphigoid vegetans with abrocitinib
Authors: Fu Chen , Zhang Quanhong , Yu Lang , Chen Liuqing , Chen Jinbo
Published: October 2024

To our knowledge, we report the first case of 43-year-old female patient with recalcitrant pemphigoid vegetans successfully treated with a combination of the selective Janus kinase 1 inhibitor abrocitinib and oral corticosteroids. After abrocitinib therapy at a dose of 100 mg per day, the itching relieved significantly within 24 h. Three months later the bullous pemphigoid disease area index decreased to 9, and both the anti-BP230 and anti-BP180 antibody levels decreased. Then the dose of prednisone tapered to 20 mg daily and abrocitinib discontinued without a relapse during follow-up.
Transforming estimated breeding values from observed to probability scale: how to make categorical data analyses more efficient
Authors: Hidalgo Jorge , Misztal Ignacy , Tsuruta Shogo , Bermann Matias , Retallick Kelli , Garcia Andre , Bussiman Fernando , Lourenco Daniela
Published: October 2024

Threshold models are often used in genetic analysis of categorical data, such as calving ease. Solutions in the liability scale are easily transformed into probabilities; therefore, estimated breeding values are published as the probability of expressing the category of main interest and are the industry’s gold standard because they are easy to interpret and use for selection. However, because threshold models involve nonlinear equations and probability functions, implementing such a method is complex. Challenges include long computing time and convergence issues, intensified by including genomic data. Linear models are an alternative to overcome those challenges. Estimated breeding values computed using linear models are highly correlated (≥0.96) with those from threshold models; however, the lack of a transformation from the observed to the probability scale limits the use of linear models. The objective of this study was to propose transformations from observed to probability scale analogous to the transformation from liability to probability scale. We assessed computing time, peak memory use, correlations between estimated breeding values, and estimated genetic trends from linear and threshold models. With 11M animals in the pedigree and almost 965k genotyped animals, linear models were 5× faster to converge than threshold models (32 vs. 145 h), and peak memory use was the same (189 GB). The transformations proposed provided highly correlated probabilities from linear and threshold models. Correlations between direct (maternal) estimated breeding values from linear and threshold models and transformed to probabilities were ≥0.99 (0.97) for all animals in the pedigree, sires with/without progeny records, or animals with phenotypic records; therefore, estimated genetic trends were analogous, suggesting no loss of genetic progress in breeding programs that would adopt linear instead of threshold models. Furthermore, linear models reduced computing time by 5-fold compared to the threshold models; this enables weekly genetic evaluations and opens the possibility of using multi-trait models for categorical traits to improve selection effectiveness.
Children Born of Conflict-Related Sexual Violence as Direct Victims under International Criminal Law
Authors: Mionki Judy
Published: October 2024

This article explores specific cases of children born of conflict-related sexual violence (CRSV) to ascertain the precise nature of their harm making them a unique category of victims under international criminal law. It will identify and illustrate, inter alia, the nature, intent and impact of their victimhood, detailing precisely how to prosecute crimes against and affecting these children at the International Criminal Court (ICC). The research eschews the conventional approach of regarding these children as secondary victims by surfacing direct crimes under ICC jurisdiction and positioning them firmly within investigative, prosecutorial and judicial attention.
Surveillance of tick-borne pathogens present in ticks (Acari: Ixodidae) removed from companion animals in Louisiana, USA
Authors: Valdes Sabrina M , Simonson Sean , Scott-Waldron Christine , Balsamo Gary , Grasperge Britton J , Foil Lane D , Balasuriya Udeni , Macaluso Kevin R
Published: October 2024

Current knowledge of tick distribution and tick-borne pathogen presence across Louisiana is limited. Collaborating with veterinarians across the state, ticks removed from companion animals were recovered and assessed for the presence of zoonotic pathogens. A large number of ticks (n = 959) were removed from companion animals and subsequently screened using qPCR for Anaplasma phagocytophilum, Babesia microti, Borrelia burgdorferi, Bartonella henselae, Ehrlichia chaffeensis, and spotted fever group Rickettsia. Five different tick species, Ixodes scapularis (54.5%), Amblyomma americanum (18.4%), Amblyomma maculatum (12.5%), Dermacentor variabilis (11.2%), and Rhipicephalus sanguineus (0.3%) from different regions of Louisiana were collected from October 2018 to July 2019. There were 15 PCR-positive ticks for Rickettsia parkeri (1.6% prevalence), and four ticks were positive for Ehrlichia chaffeensis (0.4% prevalence). This survey identifies ticks and tick-borne pathogens associated with companion animals and areas for future active surveillance.
A unified model for the clustering of quasars and galaxies at z ≈ 6
Authors: Pizzati Elia , Hennawi Joseph F , Schaye Joop , Schaller Matthieu , Eilers Anna-Christina , Wang Feige , Frenk Carlos S , Elbers Willem , Helly John C , Mackenzie Ruari , Matthee Jorryt , Bordoloi Rongmon , Kashino Daichi , Naidu Rohan P , Yue Minghao
Published: October 2024

Recent observations from the EIGER JWST program have measured for the first time the quasar–galaxy cross-correlation function at $z\approx 6$. The autocorrelation function of faint $z\approx 6$ quasars was also recently estimated. These measurements provide key insights into the properties of quasars and galaxies at high redshift and their relation with the host dark matter haloes. In this work, we interpret these data building upon an empirical quasar population model that has been applied successfully to quasar clustering and demographic measurements at $z\approx 2\!-\!4$. We use a new, large-volume N-body simulation with more than a trillion particles, FLAMINGO-10k, to model quasars and galaxies simultaneously. We successfully reproduce observations of $z\approx 6$ quasars and galaxies (i.e. their clustering properties and luminosity functions), and infer key quantities such as their luminosity–halo mass relation, the mass function of their host haloes, and their duty cycle/occupation fraction. Our key findings are (i) quasars reside on average in $\approx 10^{12.5}\, {\rm M}_{\odot }$ haloes (corresponding to $\approx 5\sigma$ fluctuations in the initial conditions of the linear density field), but the distribution of host halo masses is quite broad; (ii) the duty cycle of (UV-bright) quasar activity is relatively low ($\approx 1~{{\ \rm per\ cent}}$); (iii) galaxies (that are bright in [O iii]) live in much smaller haloes ($\approx 10^{10.9}\, {\rm M}_{\odot }$) and have a larger duty cycle (occupation fraction) of $\approx 13~{{\ \rm per\ cent}}$. Finally, we focus on the inferred properties of quasars and present a homogeneous analysis of their evolution with redshift. The picture that emerges reveals a strong evolution of the host halo mass and duty cycle of quasars at $z\approx 2\!-\!6$, and calls for new investigations of the role of quasar activity across cosmic time.
What causes the ultraviolet extinction bump at the cosmic dawn?
Authors: Li Qi , Yang X J , Li Aigen
Published: October 2024

The enigmatic ultraviolet (UV) extinction bump at 2175 $\, {\rm \mathring{\rm A}}$, the strongest spectroscopic absorption feature superimposed on the interstellar extinction curve, has recently been detected at the cosmic dawn by the JWST in JADES-GS-z6-0, a distant galaxy at redshift $z\approx 6.71$, corresponding to a cosmic age of just 800 million years after the big bang. Although small graphite grains have historically long been suggested as the carrier of the 2175 $\, {\rm \mathring{\rm A}}$ extinction bump and graphite grains are expected to have already been pervasive in the early Universe, in this work we demonstrate that small graphite grains are not responsible for the UV extinction bump seen at the cosmic dawn in JADES-GS-z6-0, as the extinction bump arising from small graphite grains is too broad and peaks at wavelengths that are too short to be consistent with what is seen in JADES-GS-z6-0.
Course and Predictors of Adult Spinal Sagittal Disorders
Authors: Mannström Heidi , Multanen Juhani , Ylinen Jari , Hautala Arto , Peuna Arttu , Karttunen Lauri , Pekkanen Liisa , Kyrölä Kati
Published: October 2024

Study Design.

Prospective case series

Objective.

To study the natural course of adult spinal deformity (ASD) over a10-year period and the determinants associated with postural malalignments.

Summary of Background Data.

ASD comprises a heterogeneous spectrum of abnormalities of the thoracolumbar spine throughout adulthood. Radiographic deterioration of sagittal alignment is a combination of decreased lumbar lordosis (LL), PI-related retroversion of the pelvic tilt (PT), anteriorizing sagittal vertical axis (SVA) and increased T1 pelvic angle (TPA).

Methods.

The full spine radiographs were taken to measure the SRS-Schwab sagittal modifiers PI-LL, PT and SVA to measure the possible change in severity of deformity from the 204 volunteer participants (mean age 62.7 years, 61% female), which were 32% of the 637 consecutive patients with prolonged back pain who originally joined the study in 2012–2013. Each participant completed the Scoliosis Research Society 22r (SRS-22r) questionnaire.

Results.

The mean change in the SRS-Schwab score was 0.4 units (baseline 1.1 vs. follow-up 1.5, P < 0.001) implying deterioration of the spinal deformity. The SRS-Schwab score decreased (n=76, 37%), remained the same (n=102, 50%) or improved (n=26, 13%). Four predictive factors for a change of sagittal alignment were found, of which the poor score in the SRS-22r function domain (P=0.049) and severe pelvic tilt (PT greater than 30°, P=0.006) predicted the change.

Conclusion.

This study showed the variability in how sagittal alignment of the spine change during the 10-year follow-up period. The ASD patients with poor self-assessed functional ability and disturbed pelvic position were associated with the risk of deterioration in spinopelvic alignment. The diversity in the natural course of ASD and the known risk factors highlights the need for tailored advice when planning preventive treatment procedures for ASD patients.

Level of evidence.

3
Impact of Respiratory Syncytial Virus and Severe Acute Respiratory Syndrome Coronavirus 2 Coinfection on Clinical Severity and Outcomes Among Children Hospitalized With Lower Respiratory Tract Infections in Soweto, South Africa
Authors: Mrubata Kitso-Lesedi , Bailie Vicky , Solomon Fatima , Izu Alane , Ncube Musawenkosi , Nunes Marta C. , Dangor Ziyaad , Madhi Shabir A. , Moore David P. , Verwey Charl
Published: October 2024

Background:

No data are available regarding the interplay and clinical manifestations of respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) coinfection in African children. We compared clinical characteristics and outcomes between RSV-only, SARS-CoV-2–only and RSV/SARS-CoV-2 coinfection lower respiratory tract infections (LRTI) in hospitalized African children.

Methods:

Prospective surveillance of children (0–59 months) hospitalized with severe LRTI was undertaken between March 1, 2020, and March 31, 2023, in Johannesburg, South Africa. Nasopharyngeal swabs for respiratory viruses and clinical data were collected, and clinical characteristics and outcomes were described and compared. Respiratory index of severity in children (RISC) scores were calculated for HIV-uninfected children, and covariates associated with high RISC scores (≥5) were evaluated.

Results:

Seven thousand four hundred fifty-six children [6.1 months (interquartile range, 14.4–18.6); 57.7% male] were enrolled, 1372 (18.4%) testing RSV+/SARS-CoV-2– (RSV only), 223 (3.0%) RSV−/SARS-CoV-2+ (SARS-CoV-2–only) and 28 (0.4%) RSV+/SARS-CoV-2+ (RSV/SARS-CoV-2 coinfection). Children with RSV only and RSV/SARS-CoV-2 coinfection were more likely to present with bronchiolitis than those with SARS-CoV-2–only (673/1372 and 15/28 vs. 46/223; P < 0.001). Children with RSV/SARS-CoV-2 coinfection had more severe disease than those with RSV or SARS-CoV-2–only, as well as a higher RISC score than SARS-CoV-2–only. Weight-for-age Z scores [adjusted risk ratio (aRR): 0.92], room air saturations (aRR: 0.988) and RSV+ status (aRR: 1.40) were independently associated with severe disease.

Conclusions:

Although both RSV and SARS-CoV-2 LRTI occurred commonly, coinfection did not. Children with RSV/SARS-CoV-2 coinfection had a higher prevalence of severe LRTI than those with RSV or SARS-CoV-2–only. These findings reinforce the urgent need for safe and effective RSV and SARS-CoV-2 vaccines, especially in children in low- and middle-income countries, where the burden of disease is the highest and the access to medical resources the lowest.
Treatment of Macrolide-resistant Mycoplasma pneumoniae Pneumonia in Children: A Meta-analysis of Macrolides Versus Tetracyclines
Authors: Bolormaa Erdenetuya , Park Ji Young , Choe Young June , Kang Cho Ryok , Choe Seung Ah , Mylonakis Eleftherios
Published: October 2024

Background:

The global prevalence of macrolide-resistant Mycoplasma pneumoniae (MRMP) pneumonia infections, particularly in children, is on the rise. It is imperative to assess the clinical efficacies of alternative antibiotics such as tetracyclines to ensure effective treatment, mitigate antibiotic resistance, enhance clinical outcomes, and minimize the spread of resistant strains among MRMP-infected children. The objective of this study was to compare the therapeutic efficacies of macrolides and tetracyclines in treating MRMP pneumonia in children.

Methods:

We systematically searched the literature to identify comparative studies that examined the clinical outcomes of macrolide and tetracycline antibiotics in children with MRMP pneumonia. We conducted a meta-analysis of the mean duration of fever, hospital stay duration, therapeutic efficacies, and time to defervescence to compare macrolides and tetracyclines.

Results:

Eleven studies involving 1143 patients compared the clinical efficacies of macrolides and tetracyclines in children with MRMP pneumonia. The studies were conducted in China, Japan, and Korea, and the outcomes of febrile days, hospital stay duration, therapeutic efficacy, and time to defervescence were analyzed. The macrolides studied were azithromycin and clarithromycin, whereas the tetracyclines included minocycline and doxycycline. The pooled estimate of 5 studies showed that the mean duration of febrile days and hospital stay was longer in the macrolides group than tetracycline group [weighted mean difference = 1.64 days, 95% confidence interval (CI): 0.68–2.59, weighted mean difference = 1.22 days, 95% CI: 0.82–1.62, respectively]. The therapeutic efficacy was significantly lower in the macrolide group than in the tetracycline group (odds ratio: 0.33, 95% CI: 0.20–0.57).

Conclusions:

The clinical efficacy of tetracycline treatment was superior to that of macrolide treatment in children with MRMP pneumonia. However, further research is required to validate these findings and inform evidence-based clinical practice guidelines.
Biomechanical corneal effects of LASIK Xtra compared with conventional FS-LASIK in high myopic eyes
Authors: Kaiser Klemens Paul , Biller Marvin Lucas , Jandewerth Tyll , Davidova Petra , Hemkeppler Eva , Lwowski Christoph , Böhm Myriam , Kohnen Thomas
Published: October 2024

Purpose:

To investigate the in vivo corneal biomechanical response to FS-LASIK combined with accelerated corneal crosslinking (LASIK Xtra) compared with conventional FS-LASIK (convLASIK) in highly myopic eyes.

Setting:

Department of Ophthalmology, Goethe-University, Frankfurt am Main, Germany.

Design:

Prospective, randomized fellow eye-controlled clinical trial.

Methods:

Patients who received treatment with LASIK Xtra (30mW/cm2, 90 seconds with continuous UV-A) in 1 eye and convLASIK in the other eye were enrolled. Both eyes were subjected preoperatively and 12 months postoperatively to a Corvis ST examination. The stiffness parameter at first applanation (SP-A1), integrated inverse radius (IIR), deformation amplitude (DA), deformation amplitude 2 mm away from apex, and the apical deformation (DARatio2mm) were evaluated.

Results:

The study included 38 high myopic eyes (−7.34 ± 1.02 diopters) of 19 patients. The results of the corneal biomechanical measurement showed a significant reduction in overall corneal stiffness with a significant decrease in postoperative SP-A1 and increase in IIR, DA, and DARatio2mm (P < .001). In a direct comparison, there was no evidence of an increase in corneal stiffness in the LASIK Xtra group compared with the convLASIK group 12 months postoperatively. No statistically significant difference was detected in any of the 4 biomechanical parameters (P > .05).

Conclusions:

The corneal biomechanical response to convLASIK and LASIK Xtra did not vary significantly. With a similar corneal thickness loss, there was no significant difference in the 4 biomechanical metrics between the convLASIK and LASIK Xtra groups. Thus, LASIK Xtra appeared not to have a protective corneal stiffening effect compared with convLASIK 12 months postoperatively.
GPR35 agonists inhibit TRPA1-mediated colonic nociception through suppression of substance P release
Authors: Gupta Rohit A. , Higham James P. , Pearce Abigail , Urriola-Muñoz Paulina , Barker Katie H. , Paine Luke , Ghooraroo Joshua , Raine Tim , Hockley James R. F. , Rahman Taufiq , St John Smith Ewan , Brown Alastair J. H. , Ladds Graham , Suzuki Rie , Bulmer David C.
Published: October 2024

The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn (CS), and phosphodiesterase inhibitor, zaprinast, are agonists at mouse GPR35, promoting the activation of different Gi/o subunits. Pretreatment with either CS or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects were lost in tissue from GPR35−/− mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlights the pronociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and sensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain.
Analgesia and peripheral c-fiber modulation by selective Nav1.8 inhibition in rhesus
Authors: Vardigan Joshua D. , Pall Parul S. , McDevitt Dillon S. , Huang ChienJung , Clements Michelle K. , Li Yuxing , Kraus Richard L. , Breslin Michael J. , Bungard Christopher J. , Nemenov Mikhail I. , Klukinov Mikhail , Burgey Chritopher S. , Layton Mark E. , Stachel Shawn J. , Lange Henry S. , Savitz Alan T. , Santarelli Vincent P. , Henze Darrell A. , Uslaner Jason M.
Published: October 2024

Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Nav1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Nav1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Nav1.8 inhibition broadly.
Sex-specific role of RNA-binding protein, pAUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury
Authors: Quijas Meranda M. , Queme Luis F. , Woodke Samantha T. , Weyler Alex A. , Buesing Dana , Butterfield Ally , Joshi Diya P. , Mitxelena-Balerdi Irati , Ulrich-Lai Yvonne M. , Jankowski Michael P.
Published: October 2024

Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. To determine how these unique gene expression programs may be established in a sex-dependent manner in a model that more closely mimics clinical scenarios, we used a developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries and compared behavioral results with unbiased and targeted screening strategies in male and female DRG. Several distinct proteins were found to be differentially expressed in male and female DRG, including phosphorylated AU-rich element RNA-binding protein (pAUF1), which is known to regulate gene expression. Nerve-specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, whereas overexpression of AUF1 in male DRG neurons increased pain-like responses. AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.
Signals in Health Inequity
Authors: Fiori Kevin P. , Levano Samantha R. , Colman Silvie , Oliveira Jason , Haughton Jessica , Lemberg Miya , Chambers Earle C. , Telzak Andrew , Spurrell-Huss Elizabeth , Sirois Adam , Stark Allison , Racine Andrew
Published: October 2024

Previous research has demonstrated that social determinants of health are drivers of medical utilization, cost, and health outcomes. In this study, we compared the mean annual total cost to deliver health services per patient by health-related social need (HRSN) status and total HRSNs using linear regression and ANOVA, respectively. Patients with ≥1 HRSN (n = 8409) yielded $1772 higher annual costs compared to patients without HRSNs (n = 34 775) (P < .0001). Compared to patients without HRSNs, delivering care to patients with 1 HRSN (n = 4222) cost $1689 (P < .0001) more and to patients with ≥2 HRSN (n = 4187) cost $1856 (P < .0001) more per year.
Comparative Outcomes of a Cognitive-Behavioral Skills Building Program on the Mental Health and Healthy Behaviors of Prenursing Students
Authors: Hoying Jacqueline , Terry Ayanna , Kelly Stephanie , Gray-Bauer Rosalind , Melnyk Bernadette Mazurek
Published: October 2024

Background:

Nursing students experience significantly more stress related diseases when compared to non-nursing students, and the state of their mental health can result in short-term increased attrition rates and increased nursing shortages.

Purpose:

A preexperimental pre-post study design was used to examine mental health and healthy behaviors among prenursing students.

Methods:

Cohorts received the MINDSTRONG© program either in-person or virtually. Data analysis included Personal Wellness Assessments completed at both pre- and poststudy for all participants (n = 110).

Results:

Both groups postintervention had statistically significant decreases in anxiety, depression, and stress and statistically significant increases in healthy lifestyle behaviors and beliefs. Students with elevated depression and anxiety scores at baseline had greater decreases postintervention than the overall groups.

Conclusion:

The outcomes for both cohorts were positive and effective in reducing stress, anxiety, and depressive symptoms. Healthy behaviors were improved and align with findings with an in-person format. Findings from this study support implementation of MINDSTRONG in synchronous sessions, either in-person or virtual.
Physical Therapy Dose After Orthopedic Multilevel Surgery Varies by Ambulatory Status in Children With Cerebral Palsy: A Pilot Study
Authors: Greve Kelly , Bailes Amy F. , Zhang Nanhua , Long Jason , Aronow Bruce , Mitelpunkt Alexis
Published: October 2024

Purpose:

To characterize physical therapy (PT) dose for children with cerebral palsy (CP) after multi-level surgery (MLS) and examine variation by ambulatory status and surgical burden.

Methods:

PT dose (Frequency, Intensity, Time, Type) data were extracted from electronic records of children with CP who received outpatient PT the year after MLS.

Results:

Seventeen children, mean 9 years, female (n=10), ambulatory (n=10), and high surgical burden (n=12) were included. In the year after surgery, 345 visits occurred. Intensity across visits was above average. Time was greatest for pre-functional activities, gait, and transitions/transfers. Types most often delivered were neuromuscular, musculoskeletal, and education/training. Ambulatory children received significantly more visits, higher intensity, and time in pre-functional activities and gait than non-ambulatory children. No differences in type by ambulatory status and PT dose by surgical burden were found.

Conclusion:

PT dose varied the first year after MLS indicating the need for guidelines by ambulatory status.

Video Abstract:

Supplemental Digital Content available at: http://links.lww.com/PPT/A516
Vault RNAs aid viral infection by facilitating nuclear export of hnRNP C and ELAVL1
Authors: Stok Jorn E. , van der Kooij Sander B. , Gravekamp Dennis , ter Haar Laurens R. , de Wolf Jasper W. , Salgado-Benvindo Clarisse , Nelemans Tessa , Grijmans Bart J.M. , Tjokrodirijo Rayman T.N. , de Ru Arnoud H. , van Veelen Peter A. , van Hemert Martijn J. , Kikkert Marjolein , van der Veen Annemarthe G.
Published: October 2024

Vault RNAs (vtRNAs) are a family of four small non-coding RNAs (ncRNAs) that are ubiquitously expressed in many eukaryotes and that regulate multiple cellular pathways. Their expression is increased upon infection with various DNA and RNA viruses. This suggests they are either co-opted by the virus to aid replication or function as an antiviral restriction factor. However, their precise molecular function remains unclear. Here, we show that replication of picornaviruses, alphaviruses, and beta-coronaviruses broadly enhances vtRNA expression. We find that genetic loss of vtRNAs inhibits replication of Sindbis virus (SINV) and encephalomyocarditis virus (EMCV), independent of the antiviral type I interferon (IFN) response. A proteomic screen uncovered the vtRNA interactome and revealed that vtRNAs associate with RNA binding proteins ELAVL1 and hnRNP C in uninfected and infected cells. VtRNAs facilitate the translocation of ELAVL1 and hnRNP C from the nucleus to the cytoplasm in infected cells, an event that is required for efficient viral replication. Moreover, hnRNP C and ELAVL1 fail to associate with viral RNA in the cytosol of SINV-infected cells in the absence of vtRNAs. Together, our findings reveal a novel molecular mechanism by which vtRNAs exert proviral activity during the course of SINV and EMCV infection, which opens up new avenues for therapeutic targeting to fight infectious diseases.
Isolation and Characterization of a Roseophage Representing a Novel Genus in the N4-like Rhodovirinae Subfamily Distributed in Estuarine Waters
Authors: Huang Xingyu , Yu Chen , Lu Longfei
Published: October 2024

Background

Roseobacteraceae, often referred to as the marine roseobacter clade (MRC), are pivotal constituents of bacterial communities in coastal and pelagic marine environments. During the past two decades, 75 roseophages that infect variousRoseobacteraceaelineages have been isolated. The N4-likeRhodovirinaesubfamily, which encompasses 15 members, represents the largest clade among these roseophages.

Results

In this study, we isolated a novel roseophage, vB_DshP-R7L, that infectsDinoroseobacter shibaeDFL12 from Xiamen Bay in the East China Sea. Conserved genes ofSchitoviridaehave been identified in the genome of vB_DshP-R7L, and following phylogenetic analysis suggest that the newly isolated phage is a member of theRhodovirinaesubfamily and is indicative of a newly proposed genus,Xianganvirus. The genome of vB_DshP-R7L harbors six auxiliary metabolic genes (AMGs), most of which potentially enhance DNAde novosynthesis. Additionally, a gene encoding ribosomal protein was identified. Comparative genomic analysis of AMG content amongRhodovirinaeindicates a distinct evolutionary history characterized by independent ancient horizontal gene transfer events. Read-mapping analysis reveals the prevalence of vB_DshP-R7L and otherRhodovirinaeroseophages in estuarine waters.

Conclusions

Our work illustrates the genomic features of a novel roseophage clade among N4-likeRhodovirinae. The AMG content of vB_DshP-R7L are under severe purification selection, which revealed their possible ecological importance. We also demonstrated that vB_DshP-R7L and otherRhodovirinaeroseophages are restrictively distributed in estuaries. Our isolation and characterization of this novel phage expand the understanding of the phylogeny, gene transfer history and biogeography of N4-likeRhodovirinaeinfecting marineRoseobacteraceae.
Cell-free immuno-profiling on a genetically programmed biochip
Authors: Dupin Aurore , Vonshak Ohad , Arad Valerie , Levanon Maya , Avidan Noa , Divon Yiftach , Peleg Steve , Thompson Seth , Noireaux Vincent , Daube Shirley S. , Bar-Ziv Roy H.
Published: October 2024

Emerging cell-free synthetic biology approaches provide biosafe, cheap, and versatile genetic tools to advance therapeutic research and development. Combined with micro-fabrication technology, we developed a platform to quantitatively reconstitute interactions of cell-free synthesized antigens with antibodies and human receptors in miniaturized compartments on a silicon chip. Photolithographic surface patterning of protein traps and on chip expression from high density gene brushes generated a continuous surface density gradient of fluorescently labeled antigens. Antibodies binding to the antigen gradient generate a full binding curve in each single compartment for affinity determination. We used the SARS-CoV-2 antigens as a model to profile the specificity and affinity of monoclonal antibodies to > 30 viral epitopes synthesized simultaneously on one chip in a genotype-phenotype linked compartments. We further profiled polyclonal antibodies in minute volumes of human sera, revealing patient-specific epitope profiles that are difficult to detect by conventional approaches. Cell-free co-synthesis of the human ACE2 receptor with the viral Receptor-Binding-Domain yielded relative binding affinities to different SARS-CoV-2 variants. This rapid, quantitative, and on-chip genetically programmed approach allows to study complex protein-protein interactions independent of protein purification steps for human immuno-profiling with a fast response time for combating emerging pathogens.
Quantum superpositions of current states in Rydberg-atom networks
Authors: Perciavalle Francesco , Rossini Davide , Polo Juan , Morsch Oliver , Amico Luigi
Published: October 2024

Quantum simulation of many-body quantum systems using Rydberg-atom platforms has become of extreme interest in the last years. The possibility to realize spin Hamiltonians and the accurate control at the single atom level paved the way for the study of quantum phases of matter and dynamics. Here, we propose a quantum optimal control protocol to engineer current states: quantum states characterized by Rydberg excitations propagating in a given spatially closed tweezer networks. Indeed, current states with different winding numbers can be generated on demand. Besides those ones with single winding number, superposition of quantum current states characterized by more winding numbers can be obtained. The single current states are eigenstates of the current operator that therefore can define an observable that remains persistent at any time. In particular, the features of the excitations dynamics reflects the nature of current states, a fact that in principle can be used to characterize the nature of the flow experimentally without the need of accessing high order correlators.

Published by the American Physical Society
2024
Exploring construction technical intelligence: a grounded theory approach to international construction professionals' adjustment in new technical contexts
Authors: Luo Jungang , Santoso Djoen San , Xu Weitao
Published: October 2024

Purpose

This study aims to investigate the process of adjustment for international construction professionals when facing new technical contexts. It introduces a framework called construction technical intelligence (CTI) and seeks to provide valuable insights and practical guidance for professionals involved in international construction projects.

Design/methodology/approach

In this study, a grounded theory approach was employed, which included conducting in-depth interviews with 28 professionals engaged in international construction projects. The qualitative data gathered from these interviews underwent systematic analysis to identify important categories and develop theoretical perspectives.

Findings

The findings demonstrate the framework of CTI, which encompasses four essential dimensions that play a significant role in facilitating the successful adjustment of international construction professionals to new technical contexts. These dimensions underscore the multidimensional nature of CTI and offer valuable insights into the necessary capabilities for professionals to thrive in dynamic and globalized construction environments.

Originality/value

By proposing this comprehensive framework, the study contributes to the knowledge and understanding of the technical adjustment process for international construction professionals. It also establishes a foundation for future quantitative research to validate and refine the proposed model, enabling a deeper comprehension of the dynamics involved in professionals' technical adjustment.
Can diplomatic activities promote foreign direct investment? Empirical evidence from China
Authors: Li Jiaen
Published: October 2024

Purpose

This study investigates the impact of Chinese senior leaders’ diplomatic visits on outward and inward foreign direct investment (OFDI and IFDI, respectively). Additionally, it aims to discern the differential impacts of diplomatic visits on FDI across different Chinese administrations.

Design/methodology/approach

We utilize data about the diplomatic visits of Chinese senior leaders to 146 host countries. The dataset was divided into two leadership eras: the tenure of President Hu Jintao and Prime Minister Wen Jiabao from 2003 to 2012 and the period from 2013 to 2021 under President Xi Jinping and Prime Minister Li Keqiang. We employ generalized least squares, lagged effect, and two-stage least squares methods to estimate the econometric model. This analytical framework assesses the influence of high-level diplomatic visits on FDI flows, addressing potential time-serial and endogeneity concerns.

Findings

The findings reveal that senior leaders’ diplomatic visits significantly boost Chinese OFDI. The effect on IFDI in China is not statistically significant. The administrations of Hu and Xi played positive roles in promoting OFDI. However, only Hu’s administration showed a statistically significant positive relationship with IFDI. The result suggests a potential increase in IFDI between China and host countries within two to three years following diplomatic visits.

Originality/value

This study contributes to the understanding of how Chinese senior leaders’ diplomatic activities affect foreign direct investment. It provides a deeper understanding of Chinese senior leaders’ diplomatic efforts to compensate for investment across two administration periods. It offers insights into the potential influence of diplomatic efforts on FDI, enriching the understanding of diplomacy’s role in international business contexts.
Input-output-outcome innovation model: an analysis of the Brazilian manufacturing companies
Authors: Lizarelli Fabiane Letícia , Ishizaka Artur Yuiti , Toledo José Carlos de
Published: October 2024

Purpose

The objectives of this study are to identify which inputs are most relevant for development and successful introduction of product and process innovations and identify the impacts of these two types of innovation on the performance of Brazilian manufacturing companies.

Design/methodology/approach

This study analyzes the relationships between input, output and outcome for a sample of 5,586 Brazilian manufacturing companies by using partial least squares structural equation modeling (PLS-SEM).

Findings

The results indicate that (1) product innovations are favored by internal resources, (2) process innovations are favored by external resources, (3) product innovations mainly affect a range of products offered by companies and (4) process innovations mainly affect performance in manufacturing capacity, flexibility and costs.

Practical implications

By identifying the main efforts to improve the innovation performance and input-output-outcome relationships, the results can contribute to a better decision-making process for innovation investments and management in companies as well as for policymakers. The results are particularly relevant given that the Brazilian case can serve as a reference for other emerging countries.

Originality/value

Analyses of the innovation in input-output-outcome relationships were performed in a comprehensive way by using a set of variables for defining each construct. This allowed each construct to be better measured, which improved the understanding of the relationships between inputs and outcomes mediated by product and process innovations.